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A link between autoimmune responses and cancer via autoantibodies was first described in the 1950's. Since, autoantibodies have been studied for their potential use as cancer biomarkers, however the exact causes of their production remain to be elucidated. This review summarises current theories of the causes of autoantibody production in cancer namely: 1) defects in tolerance and inflammation, 2) changes in protein expression levels, 3) altered protein structure and 4) cellular death mechanisms. We also highlight the need for further research into this field to improve our understanding of autoantibodies as biomarkers for cancer development and progression.
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Autoantibody Production in CancerThe Humoral Immune Response
toward Autologous Antigens in Cancer Patients
P. Zaenker
School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA, Australia
Department of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Perth, WA, Australia
abstractarticle info
Article history:
Received 18 January 2016
Accepted 23 January 2016
Available online xxxx
A link between autoimmune responses and cancer via autoantibodies was rst described in the 1950s. Since, au-
toantibodies have been studied for their potential use as cancer biomarkers, however the exact causes of their
production remain to be elucidated. This review summarizes current theories of the causes of autoantibody pro-
duction in cancer, namely: 1) defects in tolerance and inammation, 2) changes in protein expression levels, 3)
altered protein structure, and 4) cellular death mechanisms. We also highlight the need for further research into
this eld to improve our understanding of autoantibodies as biomarkers for cancer development and
© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
Autoantibody production
Immune surveillance
Humoral immune response
1. Introduction............................................................... 0
2. Tolerance defects and inammation.................................................... 0
2.1. Tolerancedefects ......................................................... 0
2.2. DownregulationofregulatoryTcells ................................................ 0
2.3. Inammation........................................................... 0
3. Changesinproteinexpressionlevels.................................................... 0
3.1. Overexpressionofthecorrespondingantigen ............................................ 0
3.2. Aberrantexpressionsiteofthecorrespondingantigen ........................................ 0
4. Alteredproteinstructure......................................................... 0
4.1. Neoepitopeexposure ....................................................... 0
4.2. Mutations ............................................................ 0
4.3. Post-translational modications .................................................. 0
5. Celldeathmechanismscauseaberrantreleaseofintracellularantigens .................................... 0
6. Concludingremarksandfutureperspectives ................................................ 0
Conictofinterest .............................................................. 0
Financialdisclosurestatement ......................................................... 0
Take-homemessages ............................................................. 0
References.................................................................. 0
Autoimmunity Reviews xxx (2016) xxxxxx
Abbreviations: dsDNA,double-strandedDNA; MIF, macrophagemigration inhibitory factor;Ang-2, angiopoietin 2; CENPF,centromere protein F; Her2/neu, human epidermal growth
factor receptor 2; MUC1, mucin 1; IMP2, insulin-like growth factor mRNA-binding family member 2; AORF, alternative open reading frame; CTAG1B/NY-ESO-1, cancer testis antigen 1B;
OGFr, opioid growth factor receptor; PSA, prostate-specic antigen; TNF, tumor necrosis factor; MAGEA3, melanoma antigen A3; PASD1, cancer antigen containing the PAS domain 1;
TGFβ, transforminggrowth factor beta; NKG2D, natural killer group 2 member D; ERp5, disulphide isomerase; MICA, MHC class 1 chain-relatedprotein A; CTLA4, cytotoxic T lymphocyte
associated protein 4; ATP, adenosine triphosphate; HMGB1, high mobility group B box protein 1.
Corresponding author at: Edith Cowan University, 270 Joondalup Drive, Joondalup, Perth, WA 6027, Australia. Tel.: +61 8 63045716.
E-mail address: p.zaenker@ecu. (P. Zaenker).
AUTREV-01816; No of Pages 7
1568-9972/© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (
Contents lists available at ScienceDirect
Autoimmunity Reviews
journal homepage:
Please cite this article as: Zaenker P, et al, Autoantibody Production in CancerThe Humoral Immune Response toward Autologous Antigens in
Cancer Patients, Autoimmun Rev (2016),
1. Introduction
The production of autoantibodies (AAbs) is believed to reect great-
er immunologic reactivity in cancer patients and enhanced immune
surveillance for cancer cells [1]. Since tumors originate from autologous
cells containing self-antigens, it has been suggested that it is the abnor-
mal exposure or presentation of these antigens that facilitates an auto-
immune response [2].
Over the lastfew decades, AAbs have become of particular interest as
cancer biomarkers as they can be easily extracted from serum via min-
imally invasive blood collection. Moreover, they exhibit increasedlevels
in very early cancer stages [3] and are observed in patients with several
carcinomas, including breast [4], lung [5], gastrointestinal [3], ovarian
[6], and prostate [7]. What is more, their production may precede clini-
cal conrmation of a tumor by several months or years [8].Notably,one
of the rst historical reports of anti-tumor protein p53 (p53) antibodies
indicated that the AAbs were detectable as early as 1747 months prior
to clinical tumor manifestation in uranium workers at high risk of lung
cancer development [9]. Detection of AAbs has also been reported
during the transition to malignancy [10]. Furthermore, AAbs may be
valuable biomarkers as they are stable serological proteins [11] with
high levels in serum despite low levels of the corresponding antigen
[12]. Additionally, they persist for extended periods after the corre-
sponding antigen is no longer detectable [6], at lasting concentrations
and with long half-lives in blood, due to limited proteolysis and clear-
ance from the circulation [13], making sample handling less arduous.
Studies have focused primarily on identifying AAbs as biomarkers
rather than investigating the underlying causes of their production.
However, the latter may reveal clues to the mechanisms involved ren-
dering autologous proteins immunogenic. Such studies could not only
lead to the development of novel biomarker assays, but also to the iden-
tication of novel therapeutic targets.
At present, the existence of a specic anti-tumor immune response,
referred to as cancer immunome, indicates that tumors express anti-
gens that are recognized as foreign by the host [11]. In the early stages
of carcinogenesis, this immune response is thought to occur as a result
of immune surveillance, the process by which the immune system
recognizes and destroys autologous cells that have become cancerous
[2,11]. In fact, histological examination of tumor affected tissues
revealed the presence of large populations of tissue resident and circu-
lating T and B cells that participate actively in immune surveillance [14].
As part of this surveillance, antigen presenting cells (APCs),
i.e., dendritic cells, B cells, and macrophages, engulf, lyse, and present
tumor-associated antigens (TAAs) on their cell surface for recognition
by CD4+ helper T cells. Interaction between the APC and T helper cell
triggers the APC release of cytokine and chemokine signals, resulting
in T cell activation and proliferation. B cells with high afnity for a spe-
cic TAA encounter the antigen, engulf, lyse, and also display it on their
cell surface for recognition and binding by activated T helper cells [15].
Lymphocyte recirculation into secondary lymphoid organs and periph-
eral tissue sites enhances this process, maximizing the frequency of
transformed cell TAAs encountering naïve B cells. The binding ofactivat-
ed T cells to B cell displayed TAAs initiates further release of cytokines
and chemokines leading to B cell proliferation. A vast number of B lym-
phocytes primed against the same antigen are produced, some of which
will serve as memory cells and others as effector cells that differentiate
into antibody producing plasma cells responsible for the systemic re-
lease of the appropriate antibody [16].AntibodyTAA binding thus rep-
resents the end stage of the humoral mechanism capable of initiating
the destruction of transformed cells containing the corresponding anti-
gen by, for example, labeling them (via opsonization) for faster macro-
phage recognition and phagocytosis. Direct binding of antibodies to the
antigen can also block receptors associated with tumor cell proliferation
and survival and AAbs can drive antigen uptake via dendritic cell Fc
gamma receptors, leading to antigen cross-presentation and vigorous
CD4+ and CD8+ T cell responses, complement dependent cytotoxicity,
and natural killer cell-mediated antibody-dependent cellular cytotoxic-
ity [17].
It is interesting to note that prolonged inammation and the subse-
quent tissue destruction associated with autoimmune diseases [18]
share many parallels with the humoral immune response to TAAs
[19]. In fact, a repertoire of autoantibodies is shared by autoimmune
conditions and cancer [20]. For example, 30% of all cancer patients
have circulating anti-nuclear antibodies (ANAs) in their sera [21],auto-
antibodies associated with Sjögren's syndrome, systemic sclerosis, and
systemic lupus erythematosus (SLE), while these are generally absent
or present at very low levels in healthy individuals [22].
The exact factors that contribute to an enhancement or disturbance
of immune surveillance leading to the production of autoantibodies in
cancer are however still illusive, and the question remains as to how
and why cellular components may be rendered immunogenic in cancer.
Here we summarize some of the major theories surrounding the pro-
duction of autoantibodies in cancer (Fig. 1), including loss of tolerance,
inammation, and changes in antigen expression, as well as their
altered exposure or altered presentation, reduced degradation, post-
translational modications (PTMs), and their aberrant location or
altered structure.
2. Tolerance defects and inammation
2.1. Tolerance defects
Approximately half of the lymphocyte population present in gener-
ative lymphoid organs is capable of binding to autoantigens [20].In
order to eliminate self-reactive lymphocytes entering the general circu-
lation, all immature lymphocytes must undergo a series of checkpoints
with processes aimed at maintaining central tolerance (tolerance to
self). Lymphocytes will only mature successfully if they are non-
reactive to autologous antigens and possess functional polypeptide
chains necessary to build a functional pre-antigen receptor, pre-BCR,
and pre-TCR for B and T cells, respectively. Self-reactive lymphocytes
are either eliminated, by negative selection via clonal deletion facilitated
apoptosis [23] or converted into a non-reactive state of clonal anergy
[24]. Alternatively, they may be preserved by positive selection,
Fig. 1. Proposed causes of autoantibody production in cancer.
2P. Zaenker et al. / Autoimmunity Reviews xxx (2016) xxxxxx
Please cite this article as: Zaenker P, et al, Autoantibody Production in CancerThe Humoral Immune Response toward Autologous Antigens in
Cancer Patients, Autoimmun Rev (2016),
provided their antigen receptor alteration is induced, also known as re-
ceptor editing or revision [25]. Self-reactive B cells that have escaped
primary developmental checkpoints are further controlled by additional
peripheral checkpoints such as germinal center arrest [26]. However,
the processes of maintaining central tolerance are complex and subject
to error. For example, maintenance of clonal anergy is problematic as it
requires constant receptor occupancy and signalling, and is easily re-
versed by dissociation of the corresponding self-antigen, resulting in
anergic self-reactive B cells regaining responsiveness and potentially
leading to the production of autoantibodies [27]. It is also believed
that inappropriate survival of auto reactive lymphocytes by escape
from clonal deletion results when their corresponding antigen is
expressed at levels not high enough to induce clonal deletion [15,16].
Additionally, autoantibodies generated against autologous nuclear
antigens are frequently found in cancer patient sera. Nuclear antigens
are structurally disordered and their intrinsic proteolytic instability
has been suggested to interfere with the binding efciency to major his-
tocompatibility complex (MHC) class II receptors throughout the elim-
ination of self-reactive lymphocytes, enabling their escape from the
primary lymphoid organs. Exposure of some autologous nuclear anti-
gens to the immune system, i.e., following tumor cell lysis, may there-
fore result in the production of autoantibodies [28].
2.2. Downregulation of regulatory T cells
High titers of AAbs have been associated with regulatory T cell
(Treg) downregulation. In fact, delayed tumor growth due to a reduc-
tion of Tregs has been correlated with an increase in effector T helper
cells, germinal center B cells, and high titers of autoantibodies [29],
such as anti-double-stranded DNA (dsDNA), ANAs, macrophage migra-
tion inhibitory factor (MIF), and angiopoietin 2 (Ang-2) antibodies, in-
dicating a robust anti-tumor response in conjunction with cell-
mediated immune response mechanisms [30].
In a recent study, Alvarez Arias et al. [30] utilized Qa-1 (HLA-E in
humans) knock-in B6 Qa-1 D227 mice that harbor a point mutation in
the MHC class Ib molecule, capable of impairing binding of CD8+ Treg
subsets to the T cell receptor (TCR) leading to impairment of the Treg
suppressive activity. B6-DK mice were inoculated with B16 melanoma
cells engineered to express the B16-OVAovalbumin transgene. In-
creased titers of anti-OVA antibodies and substantially delayed tumor
growth were observed in transgenic mice compared to wild-type con-
trol mice. Furthermore, passive transfer of antibodies from the treated
B6-DK mice into a new cohort of mice highlighted that these autoanti-
bodies could curtail tumor growth, with 60% of these mice remaining
tumor free. By contrast, mice treated with autoantibodies from B6
wild-type mice developed tumors over time [30]. Thus, the downregu-
lation of Tregs and an imbalanced CD8+ Treg/T helper cell ratio in favor
of the effector T helper cells appeared responsible for the increase in
protective autoantibody production (Fig. 2) in this model [30]. It may
be possible that the reduced production of Tregs or similar Treg
downregulatory mechanisms exist in human melanoma or other can-
cers, rendering Treg/TCR binding ineffective and promoting autoanti-
body production in some cancer patients, with potential benecial
2.3. Inammation
Autoimmune responses, such as the production of autoantibodies,
may be part of a chronic inammatory response toward cancer cells
and are associated with an array of immunological pathways, including
the releaseof several cytokines discussed in later sections. Inammation
may be maintained throughout the duration of the cancer and increases
the permeability of the nearby vasculature, thereby enabling easier ac-
cess of immune cells to the site of the malignancy [30].
An induction of inammation in the tumor microenvironment has
been suggested to facilitate the release of intracellular antigens resultin g
in abnormal exposure of autologous antigens to the immune system,
which may provide an explanation for the vast number of autoanti-
bodies produced against intracellular antigens in cancer patients [28].
The tumor inammatory microenvironment has therefore, along with
changes in expression patterns of corresponding antigens, been
regarded as one of the main causes of autoantibody production in
cancer patients [31].
Fig. 2. Downregulation of Tregs correlates with high titers of autoantibodies and delayed tumor growth.
3P. Zaenker et al. / Autoimmunity Reviews xxx (2016) xxxxxx
Please cite this article as: Zaenker P, et al, Autoantibody Production in CancerThe Humoral Immune Response toward Autologous Antigens in
Cancer Patients, Autoimmun Rev (2016),
3. Changes in protein expression levels
3.1. Overexpression of the corresponding antigen
Most TAAs are non-mutated antigens thatare produced at low levels
in healthy cells and overexpressed during tumorigenesis, thus causing
immunogenicity presumably by presentation of their antigenic peptides
on human leukocyte antigen (HLA) class I molecules, at levels high
enough to exceed the engaged TCR threshold required for CD4+ T cell
activation, and thereby indirectly leading to antibody production
against these autologous antigens [32].
A recent study by Hong et al. [33] suggested that increased anti-cen-
tromere protein F (CENPF) autoantibody levels, detected in a cohort of
hepatocellular carcinoma patients, were likely produced in response
to the overexpression of the protein in these cancer cells. Similarly, a
strong correlation exists between human epidermal growth factor recep-
tor 2 (Her2/neu) overexpression, detectable in 30% of adenocarcinomas
[34], and the frequency of anti-Her2/neu antibodies found in breast can-
cer patients [35].Goodelletal.[35] reported no autoantibody occurrence
in breast cancer cases with low Her2/neu expression and 82% antibody
occurrence in cases with high target protein expression levels.
Mucin 1 (MUC1) is an integral membrane protein whose expression
is normally conned to the apical surface of breast ductal epithelium, a
site that is relatively isolated from the immune system. MUC1 overex-
pression is detectable in 90% of all adenocarcinomas and is associated
with increased aggressiveness of the tumor [36]. MUC1 autoantibodies,
commonly detected in breast adenocarcinoma patients, are thought to
be produced in response to overexpression of this target antigen [36].
Interestingly, the binding of antibodies to MUC1 is suggested to have
an inhibiting effect on tumor invasive functions [37].
In early-stage ovarian cancer, p53-specicantibodiesareproduced
due to the presence of mutant p53 in these tumors [38].Arecent
study by Anderson et al. [6], compared p53-specicautoantibodypro-
duction in patients with serous ovarian cancer to patients with non-
serous ovarian cancer type and found that in the latter cases, p53 anti-
bodies were still detectable but at much lower levels than in those
with serous ovarian cancer, consistent with the lower frequency of
p53 mutations in non-serous tumors [39]. Studies have demonstrated
that the half-life of mutant p53 is markedly increased to several hours
while the wild-type p53 displays a half-life of only a few minutes,
resulting in aberrant accumulation of mutated p53 in the cell nucleus.
Notably, immunogenic epitopes have been mapped primarily to both
the N- and C-terminal portions of p53, but not to the central portion
of the molecule which harbors the mutations, suggesting that the accu-
mulation of the protein rather than the mutations per se may result in
the generation of anti-p53 autoantibodies [40].
3.2. Aberrant expression site of the corresponding antigen
Autoantibody production in cancer patients may also be due to ex-
pression of the protein in an aberrant location.
Cancer testis (CT) expression is normally conned to distinct and
immune privileged locations within the body, such as the gametes of
the testis or ovaries and in trophoblasts of the placenta [41]. Their aber-
rant expression in somatic tissues has been associated with spontane-
ous autoantibody production in patients with various cancer types [42].
Similarly, autoantibody production against the oncofetal antigen
insulin-like growth factor mRNA-binding family member 2 (IMP2) has
been detected in the sera of 21% of hepatocellular carcinoma patients
but is not detectable in patients with precursor conditions such as
liver cirrhosis and chronic hepatitis. Oncofetal antigens are expressed
throughout prenatal development and cease expression in all tissues
shortly after birth, whereas their re-expression in adulthood has
been associated with malignant transformation. This abnormal re-
expression has been suggested to be the cause of autoantibody produc-
tion in hepatocellular carcinoma patients [43].
4. Altered protein structure
4.1. Neoepitope exposure
It has been observed that autoantibodies are largely raised against
intracellular self-antigens [28] that may be aberrantly expressed in can-
cer cells resulting in abnormal presentation of reactive neoepitopes to
theimmunesystem[44]. A neoepitope may be created by somatic mu-
tations that change the protein structure or an epitope normally located
within an unexposed region of the protein, may become exposed by a
conformational change or stereochemical alteration of the protein
structure, thus stimulating an immune response [45]. Furthermore, ge-
netic instability, a hallmark of carcinogenesis [46], results in expression
of neoantigens (containing neoepitopes) in tumor cells that in turn ini-
tiates an immune response against the tumor or the surrounding autol-
ogous tissue [47].
Certain structural motifs of antigens, including carbohydrate side
chains, multivalency, epitope repetition, highly charged cell surfaces
and coiled coils, have been found to enhance antigenicity [48]. Interest-
ingly, autoantibodies elicited as a result of modied proteins are often
able to bind to both the modied and unmodied form of the protein,
possibly due to the gradual expansion of the spectrum of specicities
recognized in B and/or T cell immune responses, also referred to as epi-
tope spreading [49].
Furthermore, naturally occurring and cancer-associated molecular
mimicry represented by the attachment of mimotopes, macromolecules
such as peptides that mimic the structure of an epitope onto an APC,
may also elicit a humoral immune response since the antibody for a
given epitope will equally recognize the mimotope [3].
4.2. Mutations
All cancers carry somatic mutations which vary in frequency de-
pending on thecancer type and its cause [50]. p53 is commonly mutated
in a variety of cancers [51]. Altered p53 proteins produced from mis-
sense mutations may have acquired neo-antigenic determinants that
stimulate antibody production [2,52]. Interestingly, despite the strong
autoantibody specicity toward mutated p53, only 2040% of patients
with cancers harboring p53 missense mutations have p53 autoanti-
bodies in their sera, indicating that other causes, such as protein accu-
mulation as mentioned previously and HLA polymorphisms, must
exist for autoantibody production to be facilitated in patients [40].
Notably, while missense point mutations leading to altered protein
products are highly correlated with production of autoantibodies,
stop, splice, and frameshift mutations do not generally appear to cause
autoantibody production in lung cancer [53]. By contrast, immunologi-
cal responses to antigens altered by frameshift mutations, have been de-
tected in colorectal cancer patients [54].
Furthermore, the translation of mRNA from an alternative open
reading frame (AORF) can lead to the generation of proteins bearing im-
munogenic determinants that can trigger humoral immune responses
in cancer patients. For example, antigenic peptides encoded from the
AORF of cancer-testis antigen 1B (CTAG1B), also known as NY-ESO-1,
have been shown to elicit immunological responses in cancer patients
[55]. Moreover, antibodies to the opioid growth factor receptor (OGFr)
protein recognize an alternative-reading frame of the molecule in pa-
tients suffering from melanoma, prostate cancer, lung cancer, breast,
and ovarian cancer [56].
4.3. Post-translational modications
Post-translational modications of proteins such as glycosylation,
methylation, phosphorylation, sumoylation, citrillination, adenosine
diphosphate-ribosylation, ubiquitination, and acetylation [57] are
known to occur aberrantly in cancer, creating a vast diversity of modi-
ed proteins and greatly expanding the number of targets for cancer-
4P. Zaenker et al. / Autoimmunity Reviews xxx (2016) xxxxxx
Please cite this article as: Zaenker P, et al, Autoantibody Production in CancerThe Humoral Immune Response toward Autologous Antigens in
Cancer Patients, Autoimmun Rev (2016),
specic autoantibody production [13]. In fact, over 140 unique amino
acid derivatives are produced as a result of post-translational modica-
tions, which can be enzyme-mediated or spontaneous and can generate
a neoepitope or enhance self-epitope presentation, inducing an im-
mune response [44,57].
The most common cancer-related changes involve glycosylation
[58] and phosphorylation [59], which can affect antigen processing,
binding, and interaction of the MHC presented antigen with the TCR,
therefore activating the T helper response needed to mount a humoral
autoantibody response. Aberrant glycosylation, for example, has been
observed in many cancers, causing the presentation of modied epi-
topes as TAAs that can override tolerance and induce antibody produc-
tion in cancer patients. Tarp et al. [60] reported the presence of
immunodominant epitopes on glycosyl moieties of mucin 1, which in-
duce a humoral immuneresponse in mucin-transgenic mice.Antibodies
recognizing specic MUC1 O-glycopeptides have been detected in ovar-
ian, breast, and prostate cancer patients [61], but MUC1 glycopeptides
are also detectable at similarfrequencies in healthy cancer-free controls
and are therefore not cancer specic[62].
5. Cell death mechanisms cause aberrant release of intracellular
How exactly the processing and metabolism of proteins can lead to
the mounting of an autoimmune response in cancer patients has yet
to be determined. Some studies have suggested that the cleavage of
known nuclear and cytoplasmic proteins during apoptosis and/or accu-
mulation due to insufcient clearance of secondary necrotic cells may
play a role [39,63,64]. The ongoing destruction of tumor cells, through-
out tumor development and progression, is thought to arise as a result
of extensive cell proliferation and cell survival producing overwhelming
cellular stresses [63], including ongoing immunological attacks, altered
protein structures, genomic instability, DNA damage, altered transcrip-
tional networks, and signal transduction, hypoxia as well as deprivation
of nutrients [64]. Cell lysis following tumor cell necrosis and autophagy
results in thespillage of autologousintracellular tumor contents into the
blood, exposing cancer-specic, cancer-associated, or neoantigens to
the immune system and effectively triggering an immune response
and the production of autoantibodies [20,65,66]. For example, the re-
lease of prostate-specic antigen (PSA) into the serum of patients
with malignant prostate tumors arisesfrom cell lysis due to a disruption
in the tissues between the p rostate gland lumen and its c apillaries, lead-
ing to anti-PSA antibody production [67].
Tumor cell lysis may also be promoted through secretion of cyto-
kines, such as tumor necrosis factor (TNF) and interferon-γ,byThelper
cells. TNF is an agent that causes tumor cell death by inducing thrombo-
sis in tumorblood vessels, resulting in high levels of interferon-sensitive
tumors releasing large numbers of cellular antigens, thereby triggering
the production of multiple autoantibodies [68]. In a case study of one
patient with hepatocellular carcinoma following radiation therapy, in-
creases in TNFαwere observed [69]. In another case study of a melano-
ma patient, increased melanoma antigen A3 (MAGEA3) autoantibody
levels as well as autoantibodies against cancer antigen containing the
PAS domain 1 (PASD1) were reported to be present in the patients
sera following intracranial stereotactic radiosurgery and the com-
mencement of Ipilimumab treatment [70].Inbothcasestudies,the
authors observed additional clearance of non-irradiated tumors, better
known as the abscopal effect, after localized radiation therapy to the
main lesion. Both the abscopal effect and an observed rise in autoanti-
body levels was suggested to be due to tumor antigen release and
cytokine production upon cell death caused by irradiation of the
tumor [69,70].
Furthermore, macrophages, and dendritic cells release immune sup-
pressive mediators such as transforming growth factor beta (TGF-β)
and interleukin-10 (IL-10), following their capture of apoptotic cells,
thereby stimulating Tregs [71]. The capture of necrotic cells on the
other hand, activates effector immune responses, includingthe humoral
response, by initiating the release of pro-inammatory cytokines such
as IL-1β, IL-6, IL-12, and IL-23, capable of attenuating the effects of
TGF-βand IL-10 [72]. Since cancer cells involve both apoptotic and ne-
crotic cell death concurrently, the immune system is faced with oppos-
ing signals of immune tolerance and immune effector responses, and as
a result, neither process gains full control.
The presentation ofTAAs on the surface of dyingtumor cells may be
responsible for directing the immune response toward an activated ef-
fector response state thereby promoting autoantibody production (Fig. 3).
Cells that have natural killer group 2 member D (NKG2D) ligands
presented on their cell surface, signal the presence of DNA damage
within the cell and thus become detectable by surveillance immune
cells [73]. In order to avoid recognition by the immune system, tumor
cells shed, mediated by disulphide isomerase (ERp5) [74], the MHC
class 1 chain-related protein A (MICA) protein leading to the downreg-
ulation of NKG2D ligands on the cell surface [75]. An interesting study
by Jinushi et al. [76] showed that patients on granulocyte macrophage
colony-stimulating factor-secreting tumor cell vaccines or cytotoxic T
lymphocyte associated protein 4 (CTLA-4) immunotherapy, generated
high titers of ERp5 and MICA antibodies and the production of these au-
toantibodies not only restored the immunologic cytotoxic attack against
tumor cellsdue to the maintenance of NKG2D ligands on the cancer cell
surface but also promoted cross-presentation of ingested tumor antigens
by ACPs, thereby further strengthening the immunological anti-tumor at-
tack. The release of additional danger signals such as adenosine triphos-
phate (ATP) and high mobility group B box protein 1 (HMGB1) from
cancer cells undergoing autophagy may further aid in tipping the scales
toward an effector immune response including AAb production [65].
Apoptotic cancer cells have also been found to present altered cleav-
age products and post-translationally modied self-proteins on surface
blebs which promote autoimmunity [77]. Additionally, regulatory de-
fects in apoptosis resulting in the maintenance of mutant/defective
cells may render these autologous cells immunogenic.
6. Concluding remarks and future perspectives
AAb levels are detectable many months prior to the clinical manifes-
tation of a tumor, persist for an extended period after removal of the
corresponding antigen bearing tumor and in many ways reect the
overall immunogenicity and immune response toward the tumor.
To provide useful insights on the interplay between the humoral im-
mune response and cancer, future studies should seek to investigate the
causes of the production of AAb biomarkers. The exact mechanisms re-
sponsible for cancer-related autoantibody production are still largely
unknown. As reviewed here, to date, several theories have been pro-
posed which include 1) tolerance defects and inammation, 2) changes
in expression levels, 3) altered protein structure, as well as 4) cellular
death mechanisms. It appears that it is the abnormal expression and/
or alteration in the structure of the corresponding antigen that is most
accountable for an immune response. However, failure of tolerance
mechanisms, inammation, and cell death affect the context in which
the antigensare presented to the immunesystem, initiatingthe produc-
tion of AAbs, in concert with other immune responses against trans-
formed cancer cells. Due to the heterogeneity of cancer cells and the
varied genetic and epigenetic differences between individual cancer
patients, it is likely that anti-cancer humoral autoimmune responses
originate from an array of such causes.
Furthermore, whether an increase or decrease in AAbs is benecial
to the overall patient survival is still controversial and seems to differ
with each AAb. For instance, increases in AAb levels may be associated
with complete tumor remission in some anti-cancer therapies [70].
While an increase of NY-ESO-1 autoantibodies has been shown to reect
increases in tumor burden in several cancers [78], decreases in AAb levels
are observed with cancer progression in some cases. The cancer progres-
sion associated drop in AAb levels has been suggested to be due to cancer
5P. Zaenker et al. / Autoimmunity Reviews xxx (2016) xxxxxx
Please cite this article as: Zaenker P, et al, Autoantibody Production in CancerThe Humoral Immune Response toward Autologous Antigens in
Cancer Patients, Autoimmun Rev (2016),
immunoediting,comprised of three phases, namely, elimination, equilib-
rium, and the escape phase, resulting in the survival of resistant, immune
tolerant metastatic cancer cells [79]. AAb levels may therefore aid in mon-
itoring the immune response when assessing the efcacy of existing and
novel therapeutic agents and may prove effective in disease stagi ng or as a
predictor of recurrences and a favorable clinical outcome.
Finally, the presence of some autoantibodies has been correlated
with indolent tumor growth and increased patient survival [80].There-
fore, understanding the causes of AAb production in different cancers
may lead to the development of novel therapeutic agents or the timely
application of existing treatments.
Conict of interest
The authors of the manuscript declare no conict of interest.
Financial disclosure statement
The author PZ receives ongoing nancial support as part of an Inspir-
ing Minds scholarship at Edith Cowan University while the other authors
did not receive any additional nancial support for this manuscript.
Take-home messages
A repertoire of AAbs is shared by autoimmune disorders and cancer.
The causes of cancer-related AAb production remain yet to be
Tolerance defects, inammation, and cell death affect TAA immune
Abnormal TAA expression and structure appear most accountable
for AAb production.
AAbs may be useful diagnostic, prognostic, and surveillance cancer
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Cancer Patients, Autoimmun Rev (2016),
... They are created not only before, but also during the formation of the cancer itself, which means that they can be potential biomarker molecules that will be involved in the diagnostic process [309]. The researchers pointed out that TAAbs have several significant advantages that outweigh their use over TAs: the response of TAAbs to TAs is often enhanced by immune responses, allowing them to be more easily detected; TAAbs are relatively stable in body fluids, unlike TAs, and, therefore, according to the researchers, they are more stable; and TAAbs are highly specific and easily detectable in small sample volumes [310][311][312]. ...
... In the literature, we can find studies indicating that neoantigens are specific to the patient and not to the tumor itself, which, according to the researchers, suggests that tumors avoid destruction due to the immune system. These properties make neoantigens increasingly recognized as key mediators of tumor-specific immune activation and they have been identified as potential targets for personalized cancer therapies (including cancer vaccines) [312,[337][338][339]. Thanks to the development of molecular biology techniques, including next-generation sequencing, and the participation of bioinformatics, it is possible to use data to predict neoantigens, most often on the basis of their affinity to MHC-I. ...
Full-text available
Lung cancer is a disease that in recent years has become one of the greatest threats to modern society. Every year there are more and more new cases and the percentage of deaths caused by this type of cancer increases. Despite many studies, scientists are still looking for answers regarding the mechanisms of lung cancer development and progression, with particular emphasis on the role of the immune system. The aim of this literature review was to present the importance of disorders of the immune system and the accompanying changes at the level of cell signaling in the pathogenesis of lung cancer. The collected results showed that in the process of immunopathogenesis of almost all subtypes of lung cancer, changes in the tumor microenvironment, deregulation of immune checkpoints and abnormalities in cell signaling pathways are involved, which contribute to the multistage and multifaceted carcinogenesis of this type of cancer. We, therefore, suggest that in future studies, researchers should focus on a detailed analysis of tumor microenvironmental immune checkpoints, and to validate their validity, perform genetic polymorphism analyses in a wide range of patients and healthy individuals to determine the genetic susceptibility to lung cancer development. In addition, further research related to the analysis of the tumor microenvironment; immune system disorders, with a particular emphasis on immunological checkpoints and genetic differences may contribute to the development of new personalized therapies that improve the prognosis of patients.
... Breakdown of self-tolerance mechanisms against autoantigens results in the initiation of antibody effects (66,67) and it is becoming clear that AAbs can mediate irAEs by causing systemic inflammation that results in cellular and tissue injury (67) (Figure 3). AAbs may also cause autoimmune phenotypes by inhibiting the function of their target proteins either by stimulating protein receptors or blocking stimulation by its natural ligand (67). ...
... Antibodies have been found that recognize several tumor and self-antigens, including overexpressed or aberrantly expressed antigens, modified proteins and intracellular molecules, and neoantigens (originating from mutations and alternative splicing events) that can drive humoral responses (66). Serum AAb levels against tumor-associated and selfantigens have been proposed as biomarkers for cancer detection (90), prognosis (91), ICI response and toxicities (reviewed here, Table 1). ...
Full-text available
The use of immune checkpoint inhibitors (ICIs) has evolved rapidly with unprecedented treatment benefits being obtained for cancer patients, including improved patient survival. However, over half of the patients experience immune related adverse events (irAEs) or toxicities, which can be fatal, affect the quality of life of patients and potentially cause treatment interruption or cessation. Complications from these toxicities can also cause long term irreversible organ damage and other chronic health conditions. Toxicities can occur in various organ systems, with common observations in the skin, rheumatologic, gastrointestinal, hepatic, endocrine system and the lungs. These are not only challenging to manage but also difficult to detect during the early stages of treatment. Currently, no biomarker exists to predict which patients are likely to develop toxicities from ICI therapy and efforts to identify robust biomarkers are ongoing. B cells and antibodies against autologous antigens (autoantibodies) have shown promise and are emerging as markers to predict the development of irAEs in cancer patients. In this review, we discuss the interplay between ICIs and toxicities in cancer patients, insights into the underlying mechanisms of irAEs, and the involvement of the humoral immune response, particularly by B cells and autoantibodies in irAE development. We also provide an appraisal of the progress, key empirical results and advances in B cell and autoantibody research as biomarkers for predicting irAEs. We conclude the review by outlining the challenges and steps required for their potential clinical application in the future.
... In the early stage of tumor development, tumor-associated antigens (TAAs) are produced due to gene mutation, abnormal expression, or abnormal modification of proteins. In addition, the death and lysis of tumor cells also release TAAs, which can stimulate the body to produce antibodies, called tumorassociated autoantibodies (10). The tumor associated autoantibodies produced by the body's immune system are stable, have a long half-life, and can exist continuously and stably in the serum. ...
... Studies have demonstrated that tumor-associated autoantibodies, such as those targeting p53, SOX-2, and CAGE-1, can be detected in the sera of patients at the early stage of tumorigenesis. Autoantibodies have high titers in the serum because, compared to tumor antigens, their abundance amplified many folds with the effect of the immune system, resulting in easy detection (10). Based on the above characteristics, tumorassociated autoantibodies have great potential for lung cancer diagnosis. ...
Full-text available
Lung cancer is the second most frequent malignancy and the leading cause of cancer-associated death worldwide. Compared with patients diagnosed at advanced disease stages, early detection of lung cancer significantly improved the 5-year survival rate from 3.3% to 48.8%, which highlights the importance of early detection. Although multiple technologies have been applied to the screening and early diagnosis of lung cancer so far, some limitations still exist so they could not fully suit the needs for clinical application. Evidence show that autoantibodies targeting tumor-associated antigens(TAAs) could be found in the sera of early-stage patients, and they are of great value in diagnosis. Methods, we identified and screened TAAs in early-stage non-small cell lung cancer(NSCLC) samples using the serological analysis of recombinant cDNA expression libraries(SEREX). We measured the levels of the 36 autoantibodies targeting TAAs obtained by preliminary screening via liquid chip technique in the training set(332 serum samples from early-stage NSCLC patients, 167 samples from patients with benign lung lesions, and 208 samples from patients with no obvious abnormalities in lungs), and established a binary logistic regression model based on the levels of 8 autoantibodies to distinguish NSCLC samples. Results, We validated the diagnostic efficacy of this model in an independent test set(163 serum samples from early-stage NSCLC patients, and 183 samples from patients with benign lung lesions), the model performed well in distinguishing NSCLC samples with an AUC of 0.8194. After joining the levels of 4 serum tumor markers into its independent variables, the final model reached an AUC of 0.8568, this was better than just using the 8 autoantibodies (AUC:0.8194) or the 4 serum tumor markers alone(AUC: 0.6948). In conclusion, we screened and identified a set of autoantibodies in the sera of early-stage NSCLC patients through SEREX and liquid chip technique. Based on the levels of 8 autoantibodies, we established a binary logistic regression model that could diagnose early-stage NSCLC with high sensitivity and specificity, and the 4 conventional serum tumor markers were also suggested to be effective supplements for the 8 autoantibodies in the early diagnosis of NSCLC.
... Indeed, somatic mutations and genomic instability result in large heterogeneity of the tumor cell proteome. Thus, the utilization of AAbs for cancer screening may present an opportunity to overcome biological heterogeneity, a major challenge in cancer biomarker research [11,38,39]. Although there are numerous studies about the identification of AAbs in the serum of cancer patients, including breast [40,41], colorectal [42][43][44], lung [45][46][47], ovarian [48][49][50], and gastrointestinal cancer [51][52][53][54], there is no study to address placental proteome as a target for monitoring cancer-associated AAbs. ...
Full-text available
Placenta-specific antigens are minimally expressed or unexpressed in normal adult tissues, while they are widely expressed in cancer. In the course of carcinogenesis, a vast array of autoantibodies (AAbs) is produced. Here, we used a quantitative approach to determine the reactivity of AAbs in the sera of patients with breast (BrC: N = 100, 100% female, median age: 51 years), gastric (GC: N = 30, 46.6% female, median age: 57 years), bladder (BC: N = 29, 34.4% female, median age: 57 years), and colorectal (CRC: N = 34, 41.1% female, median age: 51 years) cancers against first-trimester (FTP) and full-term placental proteome (TP) in comparison with age- and sex-matched non-cancer individuals. Human-on-human immunohistochemistry was used to determine reactive target cells in FTP. The effect of pregnancy on the emergence of placenta-reactive autoantibodies was tested using sera from pregnant women at different trimesters of pregnancy. Except for BC, patients with BrC (p < 0.0284), GC (p < 0.0002), and CRC (p < 0.0007) had significantly higher levels of placenta-reactive AAbs. BrC (p < 0.0001) and BC (p < 0.0409) in the early stages triggered higher autoantibody reactivity against FTP. The reactivities of BrC sera with FTP did not show an association with ER, PR, or HER2 expression. Pregnancy in the third trimester was associated with the induction of TP- and not FTP-reactive autoantibodies (=0.018). The reactivity of BrC sera with placental proteins was found to be independent of gravidity or abortion. BrC sera showed a very strong and specific pattern of reactivity with scattered cells beneath the syncytiotrophoblast layer. Our results reinforce the concept of the coevolution of placentation and cancer and shed light on the future clinical application of the placental proteome for the non-invasive early detection and treatment of cancer.
... Expression of Ag and production of AAb, regardless of disease stage, suggested that the AAbidentified tumor-associated Ags are not lost to immunoediting. In addition to expression, our finding that AAbs target PTM epitopes adds to the growing body of evidence that tumor-specific AAbs predominantly recognize nonmutated self-proteins (41)(42)(43). We were able to identify immunogenic PTMs to three of our tumor-specific AAbs, but more likely exist because we only screened for a few probable PTM modifications and only at predicted sites. ...
Small cell lung cancer (SCLC) elicits the generation of autoantibodies that result in unique paraneoplastic neurological syndromes. The mechanistic basis for the formation of such autoantibodies is largely unknown but is key to understanding their etiology. We developed a high-dimensional technique that enables detection of autoantibodies in complex with native antigens directly from patient plasma. Here, we used our platform to screen 1009 human plasma samples for 3600 autoantibody-antigen complexes, finding that plasma from patients with SCLC harbors, on average, fourfold higher disease-specific autoantibody signals compared with plasma from patients with other cancers. Across three independent SCLC cohorts, we identified a set of common but previously unknown autoantibodies that are produced in response to both intracellular and extracellular tumor antigens. We further characterized several disease-specific posttranslational modifications within extracellular proteins targeted by these autoantibodies, including citrullination, isoaspartylation, and cancer-specific glycosylation. Because most patients with SCLC have metastatic disease at diagnosis, we queried whether these autoantibodies could be used for SCLC early detection. We created a risk prediction model using five autoantibodies with an average area under the curve of 0.84 for the three cohorts that improved to 0.96 by incorporating cigarette smoke consumption in pack years. Together, our findings provide an innovative approach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunogenicity and clinical utility.
... Clinical samples like serum have been used to study autoantibodies against potential self-antigens, thus helping in early diagnostics, identifying prognostic markers and studying autoimmune disorders and systemic diseases [13]. Several studies in this field have identified potential autoantibody biomarkers for different types of tumours, including gastric cancer, lung cancer, brain tumours and breast cancer [14,15]. These autoantibodies can also detect potential antigen targets to develop immunotherapeutic treatments [16]. ...
Purpose: Colorectal cancer (CAC) has been reported as the second leading cause of cancer death worldwide. The 5-year annual survival is around 50%, mainly due to late diagnosis, striking necessity for early detection. This study aims to identify autoantibody in patients' sera for early screening of cancer. Experimental design: The study used a high-density human proteome array with approximately 17,000 recombinant proteins. Screening of sera from healthy individuals, CAC from Indian origin, and CAC from middle-east Asia origin were performed. Bio-statistical analysis was performed to identify significant autoantibodies altered. Pathway analysis is performed to explore the underlying mechanism of the disease. Results: The comprehensive proteomic analysis revealed dysregulation of 15 panels of proteins including CORO7, KCNAB1, WRAP53, NDUFS6, KRT30, and COLGALT2. Further biological pathway analysis for the top dysregulated autoantigenic proteins revealed perturbation in important biological pathways such as ECM degradation and cytoskeletal remodeling etc. CONCLUSIONS AND CLINICAL RELEVANCE: : The generation of an autoimmune response against cancer-linked pathways could be linked to the screening of the disease. The process of immune surveillance can be detected at an early stage of cancer. Moreover, AAbs can be easily extracted from blood serum through the least invasive test for disease screening. This article is protected by copyright. All rights reserved.
The second leading cause of cancer death in women worldwide is breast cancer (BC), and despite significant advances in BC therapies, a significant proportion of patients develop metastasis and disease recurrence. Currently used treatments, like radiotherapy, chemotherapy, and hormone replacement therapy, result in poor responses and high recurrence rates. Alternative therapies are therefore needed for this type of cancer. Cancer patients may benefit from immunotherapy, a novel treatment strategy in cancer treatment. Even though immunotherapy has been successful in many cases, some patients do not respond to the treatment or those who do respond relapse or progress. The purpose of this review is to discuss several different immunotherapy approaches approved for the treatment of BC, as well as different strategies for immunotherapy for the treatment of BC.
Cancer immunotherapy is a method of controlling and eliminating tumors by reactivating the body's cancer-immunity cycle and restoring its antitumor immune response. The increased availability of data, combined with advancements in high-performance computing and innovative artificial intelligence (AI) technology, has resulted in a rise in the use of AI in oncology research. State-of-the-art AI models for functional classification and prediction in immunotherapy research are increasingly used to support laboratory-based experiments. This review offers a glimpse of the current AI applications in immunotherapy, including neoantigen recognition, antibody design, and prediction of immunotherapy response. Advancing in this direction will result in more robust predictive models for developing better targets, drugs, and treatments, and these advancements will eventually make their way into the clinical setting, pushing AI forward in the field of precision oncology.
For several decades, a strong link between oncology and autoimmunity has been unveiled, and autoantibodies that are found in patient sera during tumorigenesis have emerged as exciting, alternative blood-based biomarkers that may aid in early cancer diagnosis. This chapter summarizes current autoantibody-based immunoassays, as well as previous and ongoing research in the space of diagnostic autoantibody discovery and validation, for the six most commonly diagnosed cancers globally, including breast, lung, colorectal, prostate, non-melanoma, and melanoma skin and gastric cancer. Other novel uses of autoantibody immunoassays in oncology are also discussed at the conclusion of this chapter.
Immunometabolism, a branch of biology describing the link between immunity and metabolism, is an emerging topic in cancer immunology. It is currently well accepted that B cells and tertiary lymph structures formed by them are associated with favorable outcomes when patients undergo cancer immunotherapy. Understanding the determinants of B-cell fate and function in cancer patients is necessary for improving cancer immunotherapy. Accumulating evidence points to the tumor microenvironment being a critical metabolic hurdle to an efficient antitumor B-cell response. At the same time, several B-cell-derived metabolites have recently been reported to inhibit anticancer immunity. In this literature review, key B-cell immunometabolism studies and the metabolic life of B cells were summarized. Then, we discussed the intrinsic metabolic pathways of B cells themselves and how the tumor microenvironment and B cells in tumors metabolically influence each other. Finally, we pointed out key questions to provide some inspiration for further study of the role of B-cell immunometabolism in the antitumor immune response.
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HER2 (human epidermal growth factor receptor-2; also known as erbB2) and its relatives HER1 (epidermal growth factor receptor; EGFR), HER3 and HER4 belong to the HER family of receptor tyrosine kinases. In normal cells, activation of this receptor tyrosine kinase family triggers a rich network of signaling pathways that control normal cell growth, differentiation, motility and adhesion in several cell lineages. The first tumor studied for an alteration of the HER2 oncogene is breast carcinoma, and so far the majority of studies have been performed on this oncotype. Although involvement of HER2 as a cause of human cell transformation needs to be further investigated, overexpression of the HER2 oncogene in human breast carcinomas has been associated with a more aggressive course of disease. It has been suggested that this association depends on HER2-driven proliferation, vessel formation and/or invasiveness; however, poor prognosis may not be directly related to the presence of the oncoprotein on the cell membrane but instead to the breast carcinoma subset identified by HER2 overexpression and characterized by a peculiar gene expression profile, as recently identified. HER2-positive tumors were recently shown to benefit from anthracyclin treatment and to be resistant to endocrine therapy. Despite the fact that many pathways interacting with HER2 are still not fully understood, this tyrosine kinase receptor is, to date, a promising molecule for targeted therapy.
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Tumor growth is associated with the inhibition of host antitumor immune responses that can impose serious obstacles to cancer immunotherapy. To define the potential contribution of Qa-1-restricted CD8 regulatory T cells (Treg) to the development of tumor immunity, we studied B6.Qa-1 D227K mice that harbor a point mutation in the MHC class Ib molecule Qa-1 that impairs CD8 Treg suppressive activity. Here, we report that the growth of B16 melanoma is substantially delayed in these Qa-1-mutant mice after therapeutic immunization with B16 melanoma cells engineered to express granulocyte macrophage colony-stimulating factor compared with Qa-1 B6-WT controls. Reduced tumor growth is associated with enhanced expansion of follicular T helper cells, germinal center B cells, and high titers of antitumor autoantibodies, which provoke robust antitumor immune responses in concert with tumor-specific cytolytic T cells. Analysis of tumor-infiltrating T cells revealed that the Qa-1 DK mutation was associated with an increase in the ratio of CD8(+) T effectors compared with CD8 Tregs. These data suggest that the CD8(+) T effector-Treg ratio may provide a useful prognostic index for cancer development and raise the possibility that depletion or inactivation of CD8 Tregs represents a potentially effective strategy to enhance antitumor immunity. Cancer Immunol Res; 2(3); 207-16. ©2013 AACR.
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BACKGROUND: This study examined the value of serum p53 autoantibodies (p53-AAb) as detection and prognostic biomarkers in ovarian cancer. METHODS: p53-AAb were detected by ELISA in sera obtained preoperatively from women undergoing surgery for a pelvic mass. This group included women subsequently diagnosed with invasive serous ovarian cancer (n = 60), nonserous ovarian cancers (n = 30), and women with benign disease (n = 30). Age-matched controls were selected from the general population (n = 120). Receiver operating characteristic curves were constructed to compare the values of p53-AAb, CA 125, and HE4 as a screening biomarker. Kaplan-Meier curves and Cox proportional hazards modeling were used to assess its prognostic value on survival. RESULTS: p53-AAb were detected in 25 of 60 (41.7%) of serous cases, 4 of 30 (13.3%) nonserous cases, 3 of 30 (10%) benign disease cases, and 10 of 120 (8.3%) controls (combined P = 0.0002). p53-AAb did not significantly improve the detection of cases [area under the curve (AUC), 0.69] or the discrimination of benign versus malignant disease (AUC, 0.64) compared with CA 125 (AUC, 0.99) or HE4 (AUC, 0.98). In multivariate analysis among cases, p53-AAb correlated only with a family history of breast cancer (P = 0.01). Detectable p53 antibodies in pretreatment sera were correlated with improved overall survival (P = 0.04; hazard ratio, 0.57; 95% confidence interval, 0.33-0.97) in serous ovarian cancer. CONCLUSIONS: Antibodies to p53 are detected in the sera of 42% of patients with advanced serous ovarian cancer. IMPACT: Although their utility as a preoperative diagnostic biomarker, beyond CA 125 and HE4, is limited, p53-AAb are prognostic for improved overall survival
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Autoimmune diseases are thought to be initiated by exposures to foreign antigens that cross-react with endogenous molecules. Scleroderma is an autoimmune connective tissue disease in which patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, we hypothesized that the “foreign” antigens in this autoimmune disease are encoded by somatically mutated genes in the patients’ incipient cancers. Studying cancers from scleroderma patients, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to RPC1 but not in eight patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. These results offer insight into the pathogenesis of scleroderma and provide support for the idea that acquired immunity helps to control naturally occurring cancers.
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The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.
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All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
To determine the fate of anti-DNA antibody-bearing B cells in normal mice, we generated transgenic mice bearing the heavy (H) and light (L) chain genes of a well-characterized anti-double-stranded DNA antibody. This antibody was originally isolated from a diseased MRL/lpr mouse and has characteristics common to spontaneously arising anti-DNA antibodies. Results show that the H/L transgene (tg) immunoglobulin receptor is not expressed by animals bearing both tgs, although single tg animals (H or L) express their transgenes. Young H/L tg animals express few B cells, whereas adult H/L tg animals maintain almost normal B cell numbers. Analysis of the immunoglobulin receptors used by adult B cells shows that all contain the tg H chain in association with endogenous L chains. These B cells transcribe the L tg as well as the rearranged endogenous L chain gene, and loss of endogenous L chain gene transcription results in resurrection of the 3H9 H/L tg product. Examination of the endogenous L chains used by these cells shows that they represent a highly restricted subset of V genes. Taken together, these data suggest that autoreactive transgenic B cells can rearrange endogenous L chain genes to alter surface receptors. Those L chains that compete successfully with the L tg for H chain binding, and that create a nonautoreactive receptor, allow the B cell to escape deletion. We suggest that this receptor editing is a mechanism used by immature autoreactive B cells to escape tolerance.
Circulating autoantibodies produced by the patient's own immune system after exposure to cancer proteins are emerging as promising biomarkers for the early detection of cancer. An advantage of autoantibodies in cancer detection is their production in large quantities, despite the presence of a relatively small amount of the corresponding antigen. Autoantibodies are also expected to have persistent concentrations and long half-lives due to limited proteolysis and clearance from the circulation. Here, we review current methods for the broad screening of cancer-specific autoantibody targets and the use of such targets to develop clinically relevant assays for the detection of cancer.
Regulation throughout B cell maturation and activation prevents autoreactive B cells from entering germinal center (GC) reactions. This study shows that a subset of autoreactive B cells in V H 3H9μ IgH transgenic mice escapes these serial checkpoints and proceeds into splenic GC. GC B cells isolated from these mice all express the transgenic V H 3H9μ heavy chain, some co-express light chains that yield an anti-dsDNA specificity and some have somatic mutations, consistent with their GC origin. Nonetheless, B cell tolerance is ultimately preserved as serum titers of anti-dsDNA antibodies are not elevated. These observations suggest that those autoreactive GC B cells that escaped earlier checkpoints and possibly also those cells that acquire autoreactivity de novo by mutating their antigen receptor are arrested within the splenic GC before differentiating further Into antibody-secreting plasma cells.
Sera from patients with ovarian cancer contain autoantibodies (AAb) to tumor-derived proteins that are potential biomarkers for early detection. To detect AAb, we probed high-density programmable protein microarrays (NAPPA) expressing 5,177 candidate tumor antigens with sera from patients with serous ovarian cancer (n=34 cases/30 controls) and measured bound IgG. Of these, 741 antigens were selected and probed with an independent set of ovarian cancer sera (n=58 cases/60 controls). Twelve potential autoantigens were identified with sensitivities ranging from 13-22% at >93% specificity. These were retested using a Luminex bead arrays using 60 cases and 60 controls, with sensitivities ranging from 0-31.7% at 95% specificity. Three AAb (p53, PTPRA, and PTGFR) had area under the curve (AUC) levels>60% (p<0.01), with the partial AUC (SPAUC) over 5 times greater than for a non-discriminating test (p<0.01). Using a panel of the top three AAb (p53, PTPRA, and PTGFR), if at least two AAb were positive, the sensitivity was 23.3% at 98.3% specificity. AAb to at least one of these top three antigens were also detected in 7/20 sera (35%) of patients with low CA125 levels and 0/15 controls. AAb to p53, PTPRA, and PTGFR are potential biomarkers for the early detection of ovarian cancer.