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Can Cancer Trigger Autoimmunity?

January 2014
Science 343(6167):147-8

DOI:10.1126/science.1249486

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Authors:

Michele WL Teng

A chronic autoimmune disease sometimes appears coincidently in patients with cancer. [Also see Research Article by Joseph et al. ]

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DOI: 10.1126/science.1249486

, 147 (2014);343 Science

Michele W. L. Teng and Mark J. Smyth

Can Cancer Trigger Autoimmunity?

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www.sciencemag.org SCIENCE VOL 343 10 JANUARY 2014 147

PERSPECTIVES

Autoimmune diseases occur when

immune B and T cells fail to distin-

guish the body’s own proteins as self

and attack them, ultimately damaging tissues

and organs. There are many possible causes

of autoimmune diseases, such as chemical

exposures, infections, and genetic factors.

On page 152 of this issue, Joseph et al. ( 1)

raise another possibility—nascent growing

cancers might express new proteins (neoanti-

gens) whose exposure to the immune system

creates the potential for an autoimmune dis-

ease to develop.

Systemic sclerosis (scleroderma) is a

rare chronic autoimmune rheumatic dis-

ease associated with ﬁ brosis of the skin and

widespread destruction of blood vessels that

affects organs, with life-threatening conse-

quences. Some rheumatic diseases are also

paraneoplastic—they are present with can-

cers—and removal of the tumor or its medi-

cal treatment causes regression of the clini-

cal manifestations. Coincidental timing of

scleroderma and cancer had been observed

in patients with autoantibodies speciﬁ c for

RNA polymerase III subunit (RPC1) ( 2).

Joseph et al. examined tumor tissue and

blood samples from 16 scleroderma patients

with various types of cancer. Among the

eight patients who had anti-RPC1 autoanti-

bodies and coincident cancer, six had genetic

mutations—either somatic mutations or

loss of heterozygosity (only one copy of an

allele) in POLR3A (polymerase III polypep-

tide A, the gene encoding RPC1) (see the

ﬁ gure, below). The other eight patients had

autoantibodies to either topoisomerase 1

(anti-TOP1) or centromere protein B (anti-

CENPB) and developed delayed cancer.

Interestingly, all the anti-RPC1 anti-

bodies recognized wild-type and mutated

RPC1, indicating that the humoral immune

response does not directly target the area

of the mutation or discriminate between

mutant and wild-type versions of RPC1.

But some patients with scleroderma who

possessed deﬁ ned POLR3A mutations had

T cells that reacted to RPC1 protein frag-

ments produced from the mutated gene. The

reactivity was specific to the patient and

peptide, but the frequencies of these T cells

were comparable to those observed in other

autoimmune diseases. Given that POLR3A

mutations are exceedingly rare in cancer

(0.7% overall), it is unlikely that the onset

Can Cancer Trigger Autoimmunity?

CANCER

Michele W. L. Teng

1, 2 and Mark J. Smyth

1 ,2

A chronic autoimmune disease sometimes

appears coincidently in patients with cancer.

1Cancer Immunoregulation and Immunotherapy and Immu-

nology in Cancer and Infection Laboratories, QIMR Berg-

hofer Medical Research Institute, 300 Herston Road, Her-

ston, 4006 Queensland, Australia. 2School of Medicine,

University of Queensland, Herston, 4006 Queensland, Aus-

tralia. E-mail: mark.smyth@qimrberghofer.edu.au

during axonal growth and/or migration ( 5).

As neurons of different types and origins

adopt different strategies to polarize ( 6), it

will be interesting to explore whether apical

shedding is a marginal or widespread mecha-

nism in neurogenesis.

During mitosis of apical progenitors in the

mouse cortex, a ciliary remnant associates

with the centrosome at one pole of the mitotic

spindle, resulting in asymmetric inheritance

of a ciliary structure ( 7). Thus, the cilium is

partly conserved rather than dismantled dur-

ing cell division. The cell inheriting the cili-

ary remnant rapidly reconstitutes an apical

cilium and is more likely to retain apical pro-

genitor identity. Its sister produces a basolat-

eral cilium, a phenomenon associated with

basal progenitor identity. Basal progenitors’

restricted capacity to proliferate may result

from the reduced exposure of the basolat-

eral cilium to luminal mitogens ( 8). Future

research should address whether apical shed-

ding is also present in the developing cortex,

where indirect neurogenesis, through basal

progenitors, is predominant, and how shed-

ding integrates with asymmetric ciliary recy-

cling and basolateral cilia formation.

The cortex and neural tube appear to have

a remarkable plasticity of ciliary structures

during neurogenesis. Although mechanisti-

cally different, asymmetric recycling of cili-

ary remnants ( 7), differential positioning of

cilia ( 8), and dismantling of the cilium and

shedding of the ciliary membrane are many

ways for a cell to modulate the timing and

dosage of its exposure to environmental sig-

nals. These new layers of control in signal

reception are independent of the source con-

centration and may therefore contribute to the

diversity of cell fate decisions, allowing pro-

gression of neural differentiation and mainte-

nance of a pool of apical progenitors to occur

simultaneously in a niche.

References

1. R. M. Das, K. G. Storey, Science 343, 200 (2014).

2. R. M. Das, K. G. Storey, EMBO Rep. 13, 448 (2012).

3. D. L. Rousso et al., Neuron 74, 314 (2012).

4. J. P. Thiery, H. Acloque, R. Y. Huang, M. A. Nieto, Cell

139, 871 (2009).

5. P. L. Cheng, M. M. Poo, Annu. Rev. Neurosci. 35, 181

(2012).

6. Y. Hatanaka, K. Yamauchi, F. Murakami, Dev. Growth

Differ. 54, 398 (2012).

7. J. T. Paridaen, M. Wilsch-Bräuninger, W. B. Huttner, Cell

155, 333 (2013).

8. M. Wilsch-Bräuninger, J. Peters, J. T. Paridaen, W. B.

Huttner, Development 139, 95 (2012).

10.1126/science.1249497

POLR3A mutation or loss

of heterozygosity

Autoantibodies

Severe

Coincident Delayed,

~14 years later Not detectable

(occult? cured? never?)

Less severe ?

?

Anti-RPC1

Ant i-TOP1

or anti-CENPB

Scleroderma

Cancer

Yes

Anti-RPC1 Anti-RPC1

NoNo

Severe

Coincident

Coincidence. Four subsets of scleroderma patients

are shown (as observed by Joseph et al. (1)) with dif-

ferent autoantibody proﬁ les, mutations, and coin-

cident cancer.

CREDIT: V. ALTOUNIAN/SCIENCE

Published by AAAS

10 JANUARY 2014 VOL 343 SCIENCE www.sciencemag.org

148

PERSPECTIVES

of scleroderma and the cancer genomes of

these patients were unrelated, and that the

mutations, and T cell responses directed

against them, were coincidental. Rather,

POLR3A mutation in the occasional cancer

triggers the scleroderma.

According to cancer immunoediting ( 3),

the host can control tumor growth through

innate and adaptive immune mechanisms.

Genetic instability in the tumor may cre-

ate neoantigens that are recognized by the

immune system, leading to the selection of

tumor cells that can escape immune pres-

sure. Neoantigens have been demonstrated in

tumors by means of epitope prediction algo-

rithms ( 4). These principles have been dem-

onstrated in mouse models of carcinogenesis

and multistage cancer progression ( 3, 4), but

also recently, the importance of a patient’s

immune reaction with cancer in dictating

disease-free survival (immune contexture)

has been established ( 5).

The relatively low fraction of neoplas-

tic cells with genetic alterations in the can-

cers from some of the scleroderma patients

studied by Joseph et al. suggests that cancer

immunoediting had occurred. Cancer cells

targeted by T cells appear to selectively lose

the mutant allele, and loss of heterozygos-

ity occurred in most of the tumors that were

present synchronously with the scleroderma.

In some tumors, the loss of heterozygosity

was not yet complete (clonal heterogene-

ity was observed in which a small percent-

age of the tumor cells still carried the muta-

tion). Presumably, if those tumors had been

sampled a few months later, there might not

be any detectable mutant cells because loss

of heterozygosity would have been com-

plete. The loss of heterozygosity in the other

tumors without detectable mutations is quite

possibly a “historical” record of the tumors

once carrying mutations. Interestingly, no

mutant allele or loss of heterozygosity was

detected in some patients with anti-RPC1

autoantibodies, suggesting that other mech-

anisms can induce their production. The eti-

ology of scleroderma development in these

patients may resemble that in patients with

anti-TOP1 and anti-CENPB autoantibod-

ies. It is also possible that patients with

RPC1-speciﬁ c autoantibodies and no can-

cer may once have had nascent cancer or

harbor cancer in a state of immune-medi-

ated dormancy. The loss of heterozygos-

ity of POLR3A in some patients raises the

possibility that immunoediting may involve

gene copy-number alterations in the cancer.

Alternatively, because RPC1 plays a role in

sensing and limiting infection by intracellu-

lar bacteria and viruses ( 6), cancer may also

Second-closest to Jupiter (after Io) of

the four large Galilean satellites,

icy Europa is one of the strangest

objects in the solar system ( 1). On page 171

of this issue, Roth et al. ( 2) present strong

evidence for ongoing eruptions of plumes

of water vapor from Europa’s surface. This

is a potentially major discovery, making

Europa only the fourth object in the solar

system known to exhibit ongoing internally

powered geological activity, after Earth,

Europa’s volcanic neighbor moon Io, and

Saturn’s icy moon Enceladus.

Europa is slightly smaller than our own

Moon, with a radius of 1561 km and a density

of 3010 kg m–3, implying an interior mostly

composed of silicates plus about 10% water

by mass. Gravity observations by the Gali-

leo Jupiter orbiter revealed that Europa is

strongly differentiated, with the lower-density

water component concentrated near the sur-

face ( 3). The surface is dominated by water

ice, along with other hydrated species, proba-

bly salts. Europa’s surface appearance is truly

bizarre, crisscrossed with fractures, some-

times global in extent, that on closer inspec-

tion turn out to be double ridges (see the ﬁ g-

Glimpsing Eruptions on Europa

PLANETARY SCIENCE

John R. Spencer

Recent observations with the Hubble Space Telescope reveal what are probably eruptions of water

vapor from Jupiter’s moon Europa.

Southwest Research Institute, 1050 Walnut Street, Boulder,

CO 80302, USA. E-mail: spencer@boulder.swri.edu

mutate or lose POLR3A to evade activating

innate immunity.

The association between cancer and rheu-

matic diseases has been intriguing for many

years ( 7). Paraneoplastic syndromes may

be mediated by autoantibodies due either to

tumor antigens that are also expressed by

cells targeted by the autoimmune disease or

to the release of intracellular antigens from

apoptotic tumor cells ( 8). However, these

responses are directed to the normal pro-

tein, and there is yet no evidence that encod-

ing genes were mutated in the tumors. Joseph

et al. extend causation to include mutant

POLR3A in human tumors that elicits an

immune response against the mutant RPC1

but cross-reacts with the normal RPC1,

resulting in autoimmunity. However, the can-

cer mutation is likely not enough and addi-

tional factors (genetic, environmental, or

target tissue–specific) may be required to

generate damage to normal tissue.

From an epidemiological viewpoint, the

study by Joseph et al. is underpowered, but

these ﬁ ndings may also prompt research into

whether antigens other than RPC1 might

trigger autoimmunity (e.g., in myositis and

lupus). In larger studies, mining exome

sequencing data can help identify a patient’s

speciﬁ c tumor antigen proﬁ le and potential

tumor immunity and autoimmunity. How-

ever, the ﬁ ndings by Joseph et al. raise inter-

esting issues about tumors with high mutation

rates (lung, melanoma) or microsatellite DNA

instability (colorectal) and their predisposi-

tion to cause autoimmunity. Simple analysis

of large tissue collections from cancer patients

with accompanying “immunoscores” and

patient disease history might reveal correla-

tions with autoimmune syndromes.

Very little autoimmunity has been caus-

ally linked to cancer mutations and subse-

quent immune reactions, but these events

have only been examined in cancer patients

with clinically detectable disease. Do autoim-

mune patients in general have an undetectable

burden or history of cancer? New immuno-

therapeutic treatments for cancer that break

tolerance will help to clarify the underlying

natural human immune reaction to cancer and

its side effects on normal tissues.

References and Notes

1. C. G. Joseph et al., Science 343, 152 (2014); 10.1126/

science.1246886.

2. A. A. Shah, A. Rosen, L. Hummers, F. Wigley, L. Casciola-

Rosen, Arthritis Rheum. 62, 2787 (2010).

3. R. D. Schreiber, L. J. Old, M. J. Smyth, Science 331, 1565

(2011).

4. H. Matsushita et al., Nature 482, 400 (2012).

5. J. Galon et al., Science 313, 1960 (2006).

6. A. Ablasser et al., Nat. Immunol. 10, 1065 (2009).

7. J. E. Naschitz, Curr. Opin. Rheumatol. 13, 62 (2001).

8. M. L. Albert, R. B. Darnell, Nat. Rev. Cancer 4, 36 (2004)

.

Acknowledgments: M.W.L.T is supported by a CDF1 Fellow-

ship and Project Grant from the National Health and Medical

Research Council of Australia (NH&MRC) and Prostate Cancer

Foundation of Australia. M.J.S. is supported by a NH&MRC

Australia Fellowship and Program Grant, and Program Grant

from the Susan G. Komen for the Cure.

10.1126/science.1249486

Published by AAAS

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Mar 2011
SCIENCE

Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called “cancer immunoediting,” which integrates the immune system’s dual host-protective and tumor-promoting roles.

Close Temporal Relationship Between Onset of Cancer and Scleroderma in Patients With RNA Polymerase I/III Antibodies

Article

Sep 2010
ARTHRIT RHEUM-ARTHR

This study was undertaken to examine the temporal relationship between scleroderma development and malignancy, and to evaluate whether this differs by autoantibody status among affected patients. Study participants had a diagnosis of scleroderma, a diagnosis of cancer, cancer, an available serum sample, and a cancer pathology specimen. Sera were tested for autoantibodies against topoisomerase I, centromere, and RNA polymerase I/III by immunoprecipitation and/or enzyme-linked immunosorbent assay. Clinical and demographic characteristics were compared across autoantibody categories. Expression of RNA polymerases I and III was evaluated by immunohistochemistry using cancerous tissue from patients with anti-RNA polymerase antibodies. Twenty-three patients were enrolled. Six patients tested positive for anti-RNA polymerase I/III, 5 for anti-topoisomerase I, and 8 for anticentromere, and 4 were not positive for any of these antigens. The median duration of scleroderma at cancer diagnosis differed significantly between groups (-1.2 years in the anti-RNA polymerase I/III group, +13.4 years in the anti-topoisomerase I group, +11.1 years in the anticentromere group, and +2.3 years in the group that was negative for all antigens tested) (P = 0.027). RNA polymerase III demonstrated a robust nucleolar staining pattern in 4 of 5 available tumors from patients with antibodies to RNA polymerase I/III. In contrast, nucleolar RNA polymerase III staining was not detected in any of 4 examined tumors from the RNA polymerase antibody-negative group (P = 0.048). Our findings indicate that there is a close temporal relationship between the onset of cancer and scleroderma in patients with antibodies to RNA polymerase I/III, which is distinct from scleroderma patients with other autoantibody specificities. In this study, autoantibody response and tumor antigen expression are associated. We propose that malignancy may initiate the scleroderma-specific immune response and drive disease in a subset of scleroderma patients.

Rheumatic syndromes: Clues to occult neoplasia

Article

Feb 2001

Jochanan E Naschitz

Rheumatic disorders associated with cancer include a variety of conditions, most of which have no features distinguishing them from idiopathic rheumatic disorders. It is generally held that an extensive search for occult malignancy in most rheumatic syndromes is not recommended unless the case is accompanied by specific findings suggestive of malignancy. Within the past year information has accumulated on the role of long-standing rheumatic disorders as premalignant conditions and the role of autoantibodies as screening tests for occult cancer. The present article discusses cancer-associated rheumatic syndromes, calls attention to aspects that may suggest the presence of a hidden cancer, and examines the role of laboratory tests as clues of a possible neoplastic etiology of those syndromes.

Albert ML, Darnell RB. Paraneoplastic neurologic degenerations: keys to tumour immunity. Nat Cancer Rev; 4: 36-44

Article

Feb 2004
NAT REV CANCER

Paraneoplastic neurological degenerations (PNDs) are neurological disorders that develop in patients with cancer. PNDs are triggered by an effective antitumour immune response against neuronal antigens that are expressed in cancer cells, which subsequently develops into autoimmune neurodegenerative disease. Studying patients with PND has offered the opportunity to gain unique insights into mechanisms of tumour immunity and has provided the potential to apply this knowledge to patients with cancer in general.

Jan 2006
1960

J Galon

J. Galon et al., Science 313, 1960 (2006).

Project

The role of IL-23 in tumor progression

explore the role of IL-23 in tumor progression

Article

[Monoclonal antibody approach to the study of autoimmune diseases and cancer]

May 1988 · Rinsho byori. The Japanese journal of clinical pathology

R Kannagi

Article

Full-text available

Viruses, Autoimmunity and Diabetes Mellitus

June 1983

Our studies show, first, that in mice, a viral infection can trigger an autoimmune polyendocrine disease. Second, by hybridoma technology it is possible to isolate monoclonal autoantibodies. Thrid, a number of these autoantibodies are of the MOR type, that is, they are multiple organ reactive. Fourth, by using hybridoma technology a number of human monoclonal autoantibodies have been obtained, ... [Show full abstract] and many of these also are of the MOR type. Fifth, by using thae monoclonal antibodies to prepare immuno-affinity columns, it now should be possible to isolate and identify some of the autoantigens involved in human autoimmune diseases.

Chapter

REGULATION OF AUTOIMMUNITY BY THE MODE OF PRESENTATION OF AUTOANTIGEN TO LYMPHOCYTES

December 1977

This chapter focuses on the regulation of autoimmunity by the mode of presentation of autoantigen to lymphocytes. Autoimmune diseases are characterized by an attack of an individual's lymphocytes against its own body's components, self-antigens. In a study described in the chapter, basic protein (BP) behaved as a self-immunogen when presented to lymphocytes via syngeneic macrophages. The ... [Show full abstract] recognition of BP was detected by testing the ability of the initiator lymphocytes (IL) to specifically recruit recipient lymphocytes (RL) in highly inbred strain 13 guinea pigs. The blocking of immunogenicity by soluble BP is compatible with the concept that nonimmunogenic forms of self-antigens might help maintain natural tolerance to self by blocking lymphocyte receptors and preventing their triggering by immunogenic cell-bound forms of the self-antigens.

Article

Antigenic Mimicry, Clonal Selection and Autoimmunity

June 2001 · Journal of Autoimmunity

Irun Cohen

The triggering of autoimmunity by infection or immunization is often blamed on antigenic mimicry. But the concept of antigen mimicry impinges on our understanding of adaptive immunity in general, and not only on autoimmunity. Here are some thoughts about the consequences of immune mimicry.

Article

Autoimmune bleeding disorders in cancer patients

February 2001 · Haemostasis

Pier Mannuccio Mannucci

Last Updated: 01 Nov 2022