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The effect of chemotherapy on programmed cell death 1/ programmed cell death 1 ligand axis: Some chemotherapeutical drugs may finally work through immune response


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Most tumors are immunogenic which would trigger some immune response. Chemotherapy also has immune potentiating mechanisms of action. But it is unknown whether the immune response is associated with the efficacy of chemotherapy and the development of chemoresistance. Recently, there is a growing interest in immunotherapy, among which the co-inhibitory molecules, programmed cell death 1/programmed cell death 1 ligand (PD-1/PD-L1) leads to immune evasion. Since some reports showed that conventional chemotherapeutics can induce the expression of PD-L1, we try to summarize the effect of chemotherapy on PD-1/PD-L1 axis and some potential molecules relevant to PD-1/PD-L1 in chemoresistance in this review.
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Oncotarget29794 Oncotarget, Vol. 7, No. 20
The eect of chemotherapy on programmed cell death 1/
programmed cell death 1 ligand axis: some chemotherapeutical
drugs may nally work through immune response
Min Luo1 and Liwu Fu1
1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong
Esophageal Cancer Institute, Sun Yat-Sen University Cancer Center, Guangzhou, China
Correspondence to: Liwu Fu, email:
Keywords: programmed cell death 1, programmed cell death 1 ligand, chemotherapy, immunotherapy
Received: October 30, 2015 Accepted: February 15, 2016 Published: February 23, 2016
Most tumors are immunogenic which would trigger some immune response.
Chemotherapy also has immune potentiating mechanisms of action. But it is unknown
whether the immune response is associated with the ecacy of chemotherapy
and the development of chemoresistance. Recently, there is a growing interest in
immunotherapy, among which the co-inhibitory molecules, programmed cell death
1/programmed cell death 1 ligand (PD-1/PD-L1) leads to immune evasion. Since
some reports showed that conventional chemotherapeutics can induce the expression
of PD-L1, we try to summarize the eect of chemotherapy on PD-1/PD-L1 axis and
some potential molecules relevant to PD-1/PD-L1 in chemoresistance in this review.
Immunotherapy is a rising hope for cancer patients,
utilizing the immune system to detect and eliminate
foreign tumor antigens. But immune response is such a
complex phenomenon involving clonal T cell selection,
activation, proliferation and trafcking to antigen sites
to deliver immune effector functions, that it’s hard to hit
the target in immunotherapy [1]. The process of T cell
activation requires two major signals (Figure 1): the co-
stimulatory signals and co-inhibitory signals [2]. The
co-inhibitory signals could be a main actor in cancer
progression through the inhibition of anti-cancer immune
response [3]. One of the inhibitory signals is PD-1/PD-L1
axis. PD-1 is a member of the B7 receptor family and is
inducibly expressed on activated T cell subsets including
T follicular helper (Tfh) cells [5] and T regulatory (Treg)
cells. It attenuates immune responses by negatively
regulating T cell proliferation and function [4]. And the
relationship between PD-L1 expression on tumor and/or
immune cells and objective immune response has been
reported [6-9].
Chemotherapy is a conventional treatment for
cancer with different extent of cytotoxicity but has
immune potentiating mechanisms of action [10]. Whether
chemotherapy can stimulate immune response and nally
kill tumors is unknown. Recent introduction of immune
modulators, PD-1/PD-L1 adds much excitement to this
eld. It is reported that the expression rate of PD-L1 in
human malignant tumors varies from 19% to 92% [11]
and the expression of PD-L1 is positively correlated
with tumor progression [12-15]. PD-L1 overexpression
predicted better pathological response to chemotherapy,
independently of histo-clinical variables and predictive
gene expression signatures [16]. Zhang et al. [18]
demonstrated that paclitaxel, etoposide and 5-uorouracil
were able to induce PD-L1 surface expression in human
breast cancer cells and increase PD-L1-mediated
T cell apoptosis, revealing a potential link between
chemotherapy and cancer immunoresistance. PD-L1 is
expressed by cancer cells, the exact mechanism of how the
chemotherapeutic drugs work on tumor microenvironment
especially PD-1/PD-L1 axis and how this PD-1/PD-L1
axis induces chemoresistance is not clear. Herein, in this
review, we try to summarize the relationships between
chemotherapy and immune response through PD-1/PD-
L1 axis.
Accumulating evidences suggest that conventional
therapeutic regimens as well as targeted anticancer agents,
originate (at least in part) from their ability to elicit a novel
or reinstate a pre-existing tumor-specic immune response
[19, 20]. One of the mechanisms is that chemotherapy can
provoke the immune system to recognize and destroy
malignant cells called immunogenic cell death (ICD) [21].
Several common chemotherapeutics share the ability to
trigger ICD, (e.g., doxorubicin, epirubicin, idarubicin,
mitoxantrone, bleomycin, bortezomib, cyclophosphamide
and oxaliplatin) [21, 22] as well as some anticancer agents
that are still under preclinical or clinical development (e.g.,
some microtubular inhibitors of the epothilone family) [21,
22]. Among the various chemotherapeutic drugs that have
been tested on mice, anthracyclines are the only agents that
provide enhanced immunity to further battle with tumor
cells [23]. Recent data indicate that cyclophosphamide at
high doses have the immunosuppressive properties, while
metronomic cyclophosphamide regimens exert contrary
immunostimulatory effects [20] by selectively depleting or
inhibiting Tregs [24]. Such immunostimulatory properties
seem to, at least in part, contribute to the therapeutic
success by cyclophosphamide as a conventional
anticancer agent [25]. Importantly, many clinical studies
demonstrated that metronomic cyclophosphamide led
to improved T cell effector functions [19, 26]. Cancer
cells evade immune recognition via down-regulating
human leukocyte antigen (HLA) Class I expression,
allowing their escape from immune surveillance and
destruction [27]. While in ovarian cancer cells, low-dose
epothilone B, taxol and vinblastine greatly increased
expression of HLA Class I and HLA-A2 molecules, and
low-dose epothilone B treatment markedly increased the
expression of interferon-α, IL-1β, IL-12 and IL-6 [27]. In
the inammatory microenvironment, interferon-γ (IFN-γ)
and other inammatory cytokines, secreted by anti-
tumor Th1 cells or macrophages, may upregulate PD-L1
expression in response to immune-mediated attack [6],
to decrease the cytotoxic local immune response. Some
anti-tumor drugs can promote the cytokines (IFN, IL-6)
release to upregulate PD-L1 constitutively or in response
to inammation [6]. PD-L1 is upregulated in cancerous
cells in vitro by immune cytokines that are critical for
T cell functioning, such as IFN-γ [28], which may even
positively feedback to enhance immune tolerance in
vivo (Figure 2). Collectively, these studies indicate that
different chemotherapeutic agents have different effects on
immune system.
Besides inducing ICD, oxaliplatin are reported
to inhibit the expression of programmed death ligand 2
(PD-L2), thereby limiting immunosuppression by both
dendritic cells (DCs) and tumor cells [29]. Treatment with
paclitaxel and etoposide upregulated PD-L1 expression
Figure 1: The regulation of T cell activation. T cell receptor (TCR) recognizes the tumor antigens in the context of major
histocompatibility complex (MHC) expressed on professional antigen presenting cells (APCs). Then APCs deliver a second signal by
positive co-stimulatory molecules CD28/B7-1/B7-2 to fully activate naive T cells. CTLA-4 can bind with B7-1/B7-2 competitively to
inhibit the activation of CD28/B7-1/B7-2, resulting in inactivation of T cells. PD-1 binds with its ligands, PD-L1 and PD-L2 to attenuate
lymphocyte activation.
in breast cancer cells, resulting in co-inhibitory signals
activation [18]. Yang et al. [30] observed an increase of
PD-L1 and PD-1 antigen expression in leukemia cells
with decitabine treatment, and both PD-L1 and PD-1
expression were increased in a concentration dependent
manner. QIN et al. [31] demonstrated that when the
cisplatin concentration is less than IC50, cisplatin could
upregulate PD-L1 expression in hepatoma H22 cells.
Meanwhile, cisplatin could activate the phosphorylation
of ERK1/2, and that cisplatin-induced PD-L1 expression
is dependent of ERK1/2 phosphorylation [31]. Oki et al.
[32] observed a suppression of PD-1 expression after
treatment with panobinostat (a histone deacetylase). It
suggests that panobinostat may exert anti-tumor activity
by decreasing PD-1 expression in normal lymphocytes,
stimulating the immune reaction against lymphoma
[32]. PD-L1 and its signaling pathway appear to be a
potential therapeutic target for cancer. Interestingly, a
recent research demonstrated that PD-L1 expression
had the capability to change over time with anti-PD-L1
antibody therapy [33]. Therefore, its expression status
of a specic tumor tissue may not reect the present
immunologic phenotype of tumor. Doxorubicin is reported
to downregulate PD-L1 expression on cell surface, while
upregulate its nuclear expression in breast cancer cells
[34]. A decrease in PD-L1 expression on cell surface is
expected to increase the immunogenicity of the cancer
cells, and its translocation to the nucleus is likely to be
responsible for the anti-apoptotic impact of anthracyclines
on cancer cells and their microenvironment [34]. The
translocation of PD-L1 from the cell surface to the
nucleus induced by doxorubicin occurs concurrently with
AKT phosphorylation, but the PI3K/AKT pathway is not
involved in this process [34], which indicates that the PD-
L1 re-distribution from the cell surface to the nucleus is
regulated by two signaling, including an AKT-dependent
pathway (dominant in the nucleus) and an unknown AKT-
independent pathway (dominant on the cell surface).
Moreover, doxorubicin combined with PD-L1 knockdown
has been shown to enhance apoptosis [34]. This indicates
that its nuclear localization can enhance the anti-apoptotic
function, which may link with the apoptotic machinery
of the cell. As for the molecular mechanism of how to
regulate PD-L1 expression has yet to be understood,
but several researchers described the presence of pro-
inammation and inammation may take part in it [35].
Further studies are needed to explore the mechanism of
chemotherapy-induced PD-L1 expression in cancer cells.
Zhang et al. [18] showed that chemotherapeutic
agents potentiated IFN-γ-induced PD-L1 expression
in human breast cancer cells. All the chemotherapeutic
Figure 2: Chemotherapeutic agents inuence cytokines network in antitumor immune system. Different chemical agents
work on immune cells, leading to various cytokines released, which can affect the immune cells populations to enhance/attenuate antitumor
agents tested in the study had similar effects on PD-L1
surface expression in breast cancer cells [18], suggesting
that they may act through a common pathway (Figure 3).
IFN-γ enhances cancer immunoresistance by upregulating
the expression of PD-L1 and PKD2 (Polycystic Kidney
Disease Gene 2) in human oral squamous carcinoma cells
in both time and dose dependent manner [36]. PKD2
knockdown with shRNA / siRNA or PKD chemical
inhibitor resulted in IFN-γ production, then downregulated
the expression of PD-L1 [36]. And the activation of PKD2
can stimulate the expression of P glycoprotein (P-gp)
[37]. Inhibition of PKD2 activation could signicantly
inhibit the expression of P-gp and decrease multiple drug
resistance (MDR) in human breast cancer cells [38],
indicating that PKD2 may be an important target for
tumor biotherapy and MDR reversal. Signaling through
key proliferative pathways, like MEK/ERK and PI3K/
AKT can also increase PD-L1 expression in malignant
glioma, prostate and breast carcinoma [39, 40]. Berthon
et al. [41] conrmed that blocking MEK inhibited PD-
L1 transcription in the AML cell lines THP-1 and U937,
suggesting that MEK is an important regulator of PD-L1
expression in leukemic cells. Non-small-cell lung cancer
(NSCLC) cell lines bearing EGFR, KRAS, BRAF, ALK
or RET mutations were found with high level of PD-L1
expression, and this may be correlated with high levels of
PI3K/AKT/mTOR pathway activation. PD-L1 expression
markedly increased in a subset of patients after acquiring
resistance to getinib in EGFR-mutant NSCLC [42].
Loss of the phosphatase and tensin homolog (PTEN)
through genetic deletions or mutations accelerates PD-L1
expression in tumors [43]. Crane et al. [40] demonstrated
that PI3K activation caused by loss of PTEN function
enhanced PD-L1 protein level expression in breast cancer
cell lines. Parsa et al. [43] found an increase of the post-
transcriptional PD-L1 expression in other types of PTEN
loss cancers with the activation of the PI3K pathway. The
transformed cells can also utilize PI3K pathway to evade
the immune system by mimicking immune cells [44],
developing resistance to T cell induced apoptosis [45],
secreting immunosuppressive cytokines [46], enhancing
the immunosuppressive potential of Treg cells [47] or
emulating immune cell chemotactic responses [48].
Inhibition of PI3K or its downstream signaling molecule
AKT decreased PD-L1 expression in tumor cells and
increased cytotoxic T cells-induced killing [43]. Therefore,
Figure 3: Chemotherapeutic agents promote PD-1/PD-L1 expression through various signals. Chemotherapeutic agents
via IFN-γ-dependent and IFN-γ-independent way to upregulate PD-L1 expression by activating different signals, like RAS/RAF, PI3K/
AKT, JAK/STAT3 and release some immune suppression cytokines to attenuate antitumor immune response.
targeting PD-1/PD-L1 interaction may be enhanced when
combined with PI3K inhibitors. The complex interaction
between PI3K signal and anti-tumor immune response
needs further studies. It also represents a promising
avenue to best exploit the anti-tumor effects of clinical
PI3K inhibitors. Toso et al. [49] showed that in PTEN-null
senescent tumors, activation of the JAK2/STAT3 pathway
induced an immunosuppressive tumor microenvironment
that contributed to tumor growth and chemoresistance.
Inhibition of the JAK2/STAT3 pathway in PTEN-decient
prostate tumors led to senescence-associated cytokine
network reprogrammed, and improved the efcacy of
docetaxel-induced senescence by triggering a strong anti-
tumor immune response. Soliman et al. [37] reported
that high PD-L1 basal cell lines had lower expression of
IRF2BP2 (interferon regulatory factor 2 binding protein 2)
and higher STAT1 levels compared to those with low PD-
L1 expression. All ndings above suggest that regulation
of PD-L1 expression varies widely among cell types and
drugs targeting signal transduction pathways might have
different immunological effects in different tumors.
A research [41] showed that in ve out of nine
patients with AML, spontaneous PD-L1 expression
increased when they relapsed. Lower expression of PD-L1
was positive correlated with a tendency to longer survival
[30]. Jennifer et al. [50] found that in progressing prostate
cancer patients, more PD-L1/2+ DCs led to poorer response
to Enzalutamide (ENZ) treatment and shorter treatment
duration. They also observed that circulating PD-L1/2+
DCs signicantly increased in mice bearing Enzalutamide
resistant (ENZR) tumors compared to castration resistant
Figure 4: Some strategies for blocking PD-1/PD-L1 axis. Targeting PD-1/PD-L1 and its downstream molecules can block the
axis to activate. And siRNA can downregulate PD-L1 expression from gene level. Changing the construct of PD-1 can convert it into a
co-stimulatory molecule to enhance immune response. Target IFN-γ can decrease IFN-γ-induced PD-L1 expression. Administration of
molecules bind with PD-1/PD-L1 can interfere the binding between PD-1 and PD-L1, thus inactive the PD-1/PD-L1 axis.
prostate cancer, and ENZR tumors expressed signicantly
increasing levels of tumor-intrinsic PD-L1. Altogether,
it suggests that there are high expressions of PD-1/PD-
L1 pathway molecules in peripheral blood immune
cells in patients with ENZR castration resistant prostate
cancer (CRPC). Another research [51] showed that drug-
resistant osteosarcoma cell line KHOSR2 and virally-
derived osteoblast cell line hFOB had high (3-log) PD-
L1 gene expression, and osteosarcoma cell line SaOS
and breast cancer cell line MCF-7 had low (< 1-log)
expression. Each osteosarcoma cell line generally has
various PD-L1 expression, ranged from low to high
PD-L1 expression, with slightly higher expression from
drug-resistant variants (KHOSR2 and U-2OSTR) than
their parental cell lines (KHOS and U-2OS) [51]. Thus,
PD-1/PD-L1 blockade has the potential to overcome
resistance, and the combination therapy of chemotherapy
and PD-1/PD-L1 blockade has the potent synergistic
effects to enhance antitumor immunity. Schatton et al.
[52] identied tumorigenic human ABCB5+ MMICs (a
novel type of cancer stem cells, malignant melanoma-
initiating cells), expressing chemoresistance determinant
ABCB5 preferentially expressed PD-1 and B7-2, but
with downregulated expression of PD-L1 compared to
cells [53]. The relationship between PD-L1 and
chemoresistance determinant ABCB5 is worthy to further
study. The PD-L1
cells were demonstrated signicantly
resistant to CDDP (compound Danshen dripping pills)
and TXL (Tongxinluo) compared with the PD-L1low cells
[54]. As for the mechanism of how PD-L1 increases the
chemoresistance, Yu Fujita et al. [54] found that a miR-
197 mimic can sensitize PD-L1high drug-resistant cells to
chemotherapy, indicating that the biological interaction
between PD-L1 and chemoresistance occurs through
the microRNA regulatory cascade. The overexpression
of miR-197 induced decreased expression of PD-L1 in
NSCLC cells [54]. The miR-197/CKS1B/STAT3 axis
can drive tumor PD-L1 expression as a biomarker of
this cascade, and miR-197 replacement therapy may be
a potential treatment strategy for chemoresistant NSCLC
With its profound immunosuppressive effect, PD-1/
PD-L1 axis has been the focus of several recent studies
aiming at neutralizing its detrimental effects on T cell
anti-tumor response (Figure 4). There are now multiple
agents targeting the PD-1/PD-L1 at different stages
of clinical development [9, 55-57] (Table 1). PD-1 and
PD-L1 antibodies have shown considerable clinical
efcacy and durability across a range of malignancy
subtypes, including melanoma and lung cancer [9, 58]
and most recently in refractory Hodgkin’s disease [59],
and quite a lot of phase II studies are ongoing in prospect
(NCT02572167, NCT02181738, NCT02327078). It
decreases the metastatic risk and improves the therapeutic
response when associated with immunogenic anti-
cancer chemotherapy such as doxorubicin [60, 61]. As
some signal molecules are reported to upregulate PD-
L1 expression, the target inhibitors may be a potential
treatment (Figure 4). Other immune modulatory
agents, like IFN-α-2b, are going on clinical trials
combined with different anti-PD-1 and anti-PD-L1
antibodies (NCT01943422, NCT01608594). Nivolumab
(NCT02464657, NCT01658878), pembrolizumab
(NCT02551432), MEDI4736 (NCT02027961),
and MPDL3280A (NCT01633970, NCT02525757,
NCT02409355) are being evaluated in combination
with chemotherapies, tyrosine kinase inhibitors, or other
targeted therapies. Recently, Tang et al. [62] converted
PD-1 to a T cell co-stimulatory receptor by exchanging
its trans-membrane and cytoplasmic tail with CD28 and
4-1BB signaling domains (PD-1-CD28-4-1BB, PD-1-
ACR), which retained the ability to bind PD-L1, but
resulting in T cell activation as evidenced by the elevated
activity of PI3K/AKT, the augmentation of cytokine
Table 1: Some anti-PD-1/PD-L1 antibodies in clinical trials
Agents Alias Target Clinical trial Application Details
Nilvolumab BMS-936559,
MDX-1106 PD-1
Approved by
Melanoma, renal cell
carcinoma and non-
small cell lung cancer
Pembrolizumab MK-3475,
Lambrolizumab PD-1
Approved by
Advanced melanoma
Pidilizumab [66] CT-011 PD-1 Phase II Hematological
malignant tumor
72 patients enrolled, PFS: 0.72 (90%
CI, 0.60 to 0.82), toxicity: 23/72
(31.94%) blood and lymphatic system
MPDL3280A Atezolizumab PD-L1 Phase III
Non-small cell lung
cancer, Ongoing (NCT01846416)
MEDI4736 Durvalumab PD-L1 Phase II
Non-small cell lung
cancer Ongoing (NCT02087423)
Avelumab MSB0010718C PD-L1 Phase II
M-Merkel cell cancer
Ongoing (NCT02155647)
secretion and the increased proliferative capacity. Samuel
et al. [63] reported that CD80-Fc (the fragment of CD80
IgG) is more effective in preventing PD-1/PD-L1-induced
suppression and restoring T cell activation compared to
treatment with mAb to either PD-1 or PD-L1. Soluble
PD-1 (sPD-1) is an efcient way to bind PD-L1 and to
block PD-1/PD-L1 interactions, in conjunction with a
two-domain molecule of bronectin (CH50) in inhibiting
tumor invasion and growth in hepatoma [64]. A study [65]
showed that using short-hairpin double-stranded silencing
RNA (siRNA) to restrain the expression of PD-1 on the
cell surface of tumor-specic T cells, improved immune
responses. In addition, it remains to be seen whether
ICD inducers (e.g., doxorubicin, epirubicin, etc.) may
be advantageously combined with non-immunogenic
conventional chemotherapeutics, targeted anticancer
agents and/or immunostimulatory strategies. It is crucial
for the discovery of next-generation chemotherapeutics,
i.e., molecules that simultaneously hit cancer cells while
exerting potent immunostimulatory effect. These agents
may be particularly relevant for the development of
combinatorial chemotherapeutic regimens that actively
engage the host immune system against malignant cells.
A better understanding of how chemotherapy affects
the anti-tumor immunity and causes chemoresistance is
crucial. But it is still unknown how the signaling events
regulate the expression of these molecules in resistant
cancer cells. Blockade of the PD-1/PD-L1 pathway is
a new, promising immunotherapy for cancer. Strategic
combination of immunotherapy and chemotherapy can
effectively change the overall tumor microenvironment, as
well as immune tolerance and immune suppression, which
can maintain effective and durable anti-tumor immune
We thank Xiao-Na Fang and De-Lan Li for revising
the manuscript for better reading.
Authors have no relevant, potential conicts of
interest to declare.
The research was supported by Major State Basic
Research Development Program of China (973 Program,
No.2012CB967000) and Natural scientic Foundation of
China (No. 81473233).
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... The anti-tumor effects of chemotherapy combined with immunotherapy are multifaceted [ Figure 4A, (Luo and Fu, 2016)]. Chemotherapy augments the effect of immunotherapy by enhancing tumor cell immunogenicity, suppressing immunosuppression, and inducing an antitumor immune response (e.g., immunogenic cell death, ICD). ...
... In May 2017, the United States FDA accelerated the approval of the anti-PD-1 antibody pembrolizumab, pemetrexed and carboplatin for the first-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC) (Qu et al., 2020). The results of the clinical trials showed that the group that received the combination of chemotherapy and immunotherapy had a significantly better objective remission rate (55% vs. 29%) and prolonged progression-free survival (PFS) (13.0 vs. 8.9 months) FIGURE 4 (A) Chemotherapeutic agents influence cytokines network in the antitumor immune system (Luo and Fu, 2016). (B) An overview of the combination of phototherapy and immunotherapy (Ng et al., 2018). ...
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Immunotherapy has demonstrated great clinical success in the field of oncology in comparison with conventional cancer therapy. However, cancer immunotherapy still encounters major challenges that limit its efficacy against different types of cancers and the patients show minimal immune response to the immunotherapy. To overcome these limitations, combinatorial approaches with other therapeutics have been applied in the clinic. Simultaneously, nano-drug delivery system has played an important role in increasing the antitumor efficacy of various treatments and has been increasingly utilized for synergistic immunotherapy to further enhance the immunogenicity of the tumors. Specifically, they can promote the infiltration of immune cells within the tumors and create an environment that is more sensitive to immunotherapy, particularly in solid tumors, by accelerating tumor accumulation and permeability. Herein, this progress report provides a brief overview of the development of nano-drug delivery systems, classification of combinatory cancer immunotherapy and recent progress in tumor immune synergistic therapy in the application of nano-drug delivery systems.
... The clinical outcome of CCA treatment that relies solely on chemotherapy is currently dismal. However, gemcitabine and other chemotherapeutic drugs were found to boost PD-L1 expression, hence amplifying signals from the PD-1/PD-L1 axis [128]. As a result, this is in favor of the notion that adding ICIs to chemotherapy can improve treatment outcomes. ...
Cholangiocarcinoma (CCA) is one of the malignant tumors that has shown rapid development in incidence and mortality in recent years. Like other types of cancer, patients with CCA experience alterations in the expression of immune checkpoints, indicating the importance of immune checkpoint inhibitors in treating CCA. The results of TCGA analysis in this study revealed a marginal difference in the expression of important immune checkpoints, Programmed cell death 1 (PD-1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and their ligands in CCA samples compared to normal ones. This issue showed the importance of combination therapy in this cancer. This review considers CCA treatment and covers several therapeutic modalities or combined treatment strategies. We also cover the most recent developments in the field and outline the important areas of immune checkpoint molecules as prognostic variables and therapeutic targets in CCA.
... It is well recognized that OC displays immunologic features that provide a rationale for the use of immunotherapy. In the last few decades, there has been growing interest in the blockade of the PD-1/PD-L1 pathway and in chemotherapy drugs that enhance immunogenic cell death [88][89][90]. As tested in mice, anthracyclines are the only drugs that provide enhanced immunity by downregulating PDL-1 expression on the surface of the cell and upregulating its expression in the nucleus. ...
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(1) Background: Anthracyclines are intriguing drugs, representing one of the cornerstones of both first and subsequent-lines of chemotherapy in ovarian cancer (OC). Their efficacy and mechanisms of action are related to the hot topics of OC clinical research, such as BRCA status and immunotherapy. Prediction of response to anthracyclines is challenging and no markers can predict certain therapeutic success. The current narrative review provides a summary of the clinical and biological mechanisms involved in the response to anthracyclines. (2) Methods: A MEDLINE search of the literature was performed, focusing on papers published in the last two decades. (3) Results and Conclusions: BRCA mutated tumors seem to show a higher response to anthracyclines compared to sporadic tumors and the severity of hand–foot syndrome and mucositis may be a predictive marker of PLD efficacy. CA125 can be a misleading marker of clinical response during treatment with anthracyclines, the response of which also appears to depend on OC histology. Immunochemistry, in particular HER-2 expression, could be of some help in predicting the response to such drugs, and high levels of mutated p53 appear after exposure to anthracyclines and impair their antitumor effect. Finally, organoids from OC are promising for drug testing and prediction of response to chemotherapy.
... PD-L1 plays an important role in the evasion of immune surveillance and activation of intrinsic prosurvival pathways [51]. Moreover, some PD-L1-regulating transcription factors (e.g., HIF-1α and STAT3) are Hsp90 client proteins [46]; several anticancer therapeutics are known to elevate PD-L1 level as a drug resistance mechanism [67,68]. Considering the aforementioned points, Hsp90 inhibition may potentiate antitumor effects of chemo-or molecular targeted therapies by downregulating PD-L1 expression. ...
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Rationale: The heat shock protein (Hsp) system plays important roles in cancer stem cell (CSC) and non-CSC populations. However, limited efficacy due to drug resistance and toxicity are obstacles to clinical use of Hsp90 inhibitors, suggesting the necessity to develop novel Hsp90 inhibitors overcoming these limitations. Methods: The underlying mechanism of resistance to Hsp90 inhibitors was investigated by colony formation assay, sphere formation assay, western blot analysis, and real-time PCR. To develop anticancer Hsp90 inhibitors that overcome the signal transducer and activator of transcription 3 (STAT3)-mediated resistance, we synthesized and screened a series of synthetic deguelin-based compounds in terms of inhibition of colony formation, migration, and viability of non-small cell lung cancer (NSCLC) cells and toxicity to normal cells. Regulation of Hsp90 by the selected compound NCT-80 [5-methoxy-N-(3-methoxy-4-(2-(pyridin-3-yl)ethoxy)phenyl)-2,2-dimethyl-2H-chromene-6-carboxamide] was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis. The antitumor, antimetastatic, and anti-CSC effects of NCT-80 were examined in vitro and in vivo using various assays such as MTT, colony formation, and migration assays and flow cytometric analysis and tumor xenograft models. Results: We demonstrated a distinct mechanism in which Hsp90 inhibitors that block N-terminal ATP-binding pocket causes transcriptional upregulation of Wnt ligands through Akt- and ERK-mediated activation of STAT3, resulting in NSCLC cell survival in an autocrine or paracrine manner. In addition, NCT-80 effectively reduced viability, colony formation, migration, and CSC-like phenotypes of NSCLC cells and their sublines with acquired resistance to anticancer drugs by inducing apoptosis and inhibiting epithelial-mesenchymal transition and the growth of NSCLC patient-derived xenograft tumors without overt toxicity. With regards to mechanism, NCT-80 directly bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the interaction between Hsp90 and STAT3 and degrading STAT3 protein. Moreover, NCT-80 inhibited chemotherapy- and EGFR TKI-induced programmed cell death ligand 1 expression and potentiated the antitumor effect of chemotherapy in the LLC-Luc allograft model. Conclusions: These data indicate the potential of STAT3/Wnt signaling pathway as a target to overcome resistance to Hsp90 inhibitors and NCT-80 as a novel Hsp90 inhibitor that targets both CSCs and non-CSCs in NSCLC.
The last two decades have witnessed a major revolution in the field of tumor immunology including clinical progress using various immunotherapy strategies. These advances have highlighted the potential for approaches that harness the power of the immune system to fight against cancer. While cancer immunotherapies have shown significant clinical successes, patient responses vary widely due to the complex and heterogeneous nature of tumors and immune responses, calling for reliable biomarkers and therapeutic strategies to maximize the benefits of immunotherapy. Especially, stratifying responding individuals from non‐responders during early stages of treatment could help avoid long‐term damages and tailor personalized treatments. In efforts to develop non‐invasive means for accurately evaluating and predicting tumor response to immunotherapy, multiple affinity‐based agents targeting immune cell markers and checkpoint molecules have been developed and advanced to clinical trials. In addition, researchers have recently turned their attention to substrate and activity‐based imaging probes that can provide real‐time, functional assessment of immune response to treatment. Here, we highlight some of those recently designed probes that image functional proteases as biomarkers of cancer immunotherapy with a focus on their chemical design and detection modalities and discuss challenges and opportunities for the development of imaging tools utilized in cancer immunotherapy.
The last two decades have witnessed a major revolution in the field of tumor immunology including clinical progress using various immunotherapy strategies. These advances have highlighted the potential for approaches that harness the power of the immune system to fight against cancer. While cancer immunotherapies have shown significant clinical successes, patient responses vary widely due to the complex and heterogeneous nature of tumors and immune responses, calling for reliable biomarkers and therapeutic strategies to maximize the benefits of immunotherapy. Especially, stratifying responding individuals from non‐responders during early stages of treatment could help avoid long‐term damages and tailor personalized treatments. In efforts to develop non‐invasive means for accurately evaluating and predicting tumor response to immunotherapy, multiple affinity‐based agents targeting immune cell markers and checkpoint molecules have been developed and advanced to clinical trials. In addition, researchers have recently turned their attention to substrate and activity‐based imaging probes that can provide real‐time, functional assessment of immune response to treatment. Here, we highlight some of those recently designed probes that image functional proteases as biomarkers of cancer immunotherapy with a focus on their chemical design and detection modalities and discuss challenges and opportunities for the development of imaging tools utilized in cancer immunotherapy.
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Breast cancer is the most frequently diagnosed cancer among women worldwide. Despite the initial clinical response obtained with the widely used conventional chemotherapy, an improved prognosis for breast cancer patients has been missing in the clinic because of the high toxicity to normal cells, induction of drug resistance, and the potential immunosuppressive effects of these agents. Therefore, we aimed to investigate the potential anti-carcinogenic effect of some boron derivatives (sodium pentaborate pentahydrate (SPP) and sodium perborate tetrahydrate (SPT)), which showed a promising effect on some types of cancers in the literature, on breast cancer cell lines, as well as immuno-oncological side effects on tumor-specific T cell activity. These findings suggest that both SPP and SPT suppressed proliferation and induced apoptosis in MCF7 and MDA-MB-231 cancer cell lines through downregulation of the monopolar spindle-one-binder (MOB1) protein. On the other hand, these molecules increased the expression of PD-L1 protein through their effect on the phosphorylation level of Yes-associated protein (Phospho-YAP (Ser127). In addition, they reduced the concentrations of pro-inflammatory cytokines such as IFN-γ and cytolytic effector cytokines such as sFasL, perforin, granzyme A, Granzyme B, and granulysin and increased the expression of PD-1 surface protein in activated T cells. In conclusion, SPP, SPT, and their combination could have growth inhibitory (antiproliferative) effects and could be a potential treatment for breast cancer. However, their stimulatory effects on the PD-1/PD-L1 signaling pathway and their effects on cytokines could ultimately account for the observed repression of the charging of specifically activated effector T cells against breast cancer cells.
Multidrug resistance (MDR) is the phenomenon in which cancer cells simultaneously develop resistance to a broad spectrum of structurally and mechanistically unrelated drugs. MDR severely hinders the effective treatment of cancer and is the major cause of chemotherapy failure. ATP-binding cassette (ABC) transporters are extensively expressed in various body tissues, and actively transport endogenous and exogenous substrates through biological membranes. Overexpression of ABC transporters is frequently observed in MDR cancer cells, which promotes efflux of chemotherapeutic drugs and reduces their intracellular accumulation. Increasing evidence suggests that ABC transporters regulate tumor immune microenvironment (TIME) by transporting various cytokines, thus controlling anti-tumor immunity and sensitivity to anticancer drugs. On the other hand, the expression of various ABC transporters is regulated by cytokines and other immune signaling molecules. Targeted inhibition of ABC transporter expression or function can enhance the efficacy of immune checkpoint inhibitors by promoting anticancer immune microenvironment. This review provides an update on the recent research progress in this field.
Background Higher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs. Methods NET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0–2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity. Results Twenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37–80), 30% ECOG PS 1–2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10–100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2–24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3–4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). Conclusion Single-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.
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We retrospectively analyzed PDL1 mRNA expression in 306 breast cancer samples, including 112 samples of an aggressive form, inflammatory breast cancer (IBC). PDL1 expression was heterogeneous, but was higher in IBC than in non-IBC. Compared to normal breast samples, PDL1 was overexpressed in 38% of IBC. In IBC, PDL1 overexpression was associated with estrogen receptor-negative status, basal and ERBB2-enriched aggressive subtypes, and clinico-biological signs of anti-tumor T-cell cytotoxic response. PDL1 overexpression was associated with better pathological response to chemotherapy, independently of histo-clinical variables and predictive gene expression signatures. No correlation was found with metastasis-free and overall specific survivals. In conclusion, PDL1 overexpression in IBC correlated with better response to chemotherapy. This seemingly counterintuitive correlation between expression of an immunosuppressive molecule and improved therapeutic response may be resolved if PDL1 expression is viewed as a surrogate marker of a strong antitumor immune response among patients treated with immunogenic chemotherapy. In such patients, PDL1 inhibition could protect activated T-cells or reactivate inhibited T-cells and improve the therapeutic response, notably when associated with immunogenic chemotherapy.
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The term “immunogenic cell death” (ICD) is now employed to indicate a functionally peculiar form of apoptosis that is sufficient for immunocompetent hosts to mount an adaptive immune response against dead cell-associated antigens. Several drugs have been ascribed with the ability to provoke ICD when employed as standalone therapeutic interventions. These include various chemotherapeutics routinely employed in the clinic (e.g., doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin) as well as some anticancer agents that are still under preclinical or clinical development (e.g., some microtubular inhibitors of the epothilone family). In addition, a few drugs are able to convert otherwise non-immunogenic instances of cell death into bona fide ICD, and may therefore be employed as chemotherapeutic adjuvants within combinatorial regimens. This is the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid. Here, we discuss recent developments on anticancer chemotherapy based on ICD inducers.
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Expression of programmed cell death receptor ligand 1 (PDL1) has been scarcely studied in breast cancer. Recently PD1/PDL1-inhibitors have shown promising results in different carcinomas with correlation between PDL1 tumor expression and responses. We retrospectively analyzed PDL1 mRNA expression in 45 breast cancer cell lines and 5,454 breast cancers profiled using DNA microarrays. Compared to normal breast samples, PDL1 expression was upregulated in 20% of clinical samples and 38% of basal tumors. High expression was associated with poor-prognosis features (large tumor size, high grade, ER-negative, PR-negative, ERBB2-positive status, high proliferation, basal and ERBB2-enriched subtypes). PDL1 upregulation was associated with biological signs of strong cytotoxic local immune response. PDL1 upregulation was not associated with survival in the whole population, but was associated with better metastasis-free and overall specific survivals in basal tumors, independently of clinicopathological features. Pathological complete response after neoadjuvant chemotherapy was higher in case of PDL1 upregulation (50% versus 21%). In conclusion, PDL1 upregulation, more frequent in basal breast cancers, was associated with increased T-cell cytotoxic immune response. In this aggressive subtype, upregulation was associated with better survival and response to chemotherapy. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent promising strategy in PDL1-upregulated basal breast cancer.
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Programmed cell death ligand-1 (PD-L1) has recently gained considerable attention for its role in tumor immune escape. Here, we identify a miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer (NSCLC), independent of immunoinhibitory signals. MiR-197 is downregulated in platinum-resistant NSCLC specimens, resulting in the promotion of chemoresistance, tumorigenicity, and pulmonary metastasis in vitro and in vivo. Mechanistic investigations reveal that a miR-197-mediated CKS1B/STAT3 axis exerts tumor progression regulated by various oncogenic genes (Bcl-2, c-Myc, and cyclin D1), and PD-L1 is a putative biomarker of this axis. Furthermore, we demonstrate that a miR-197 mimic sensitizes PD-L1highdrug-resistant cells to chemotherapy. These results indicate that the biological interaction between PD-L1 and chemoresistance occurs through the microRNA regulatory cascade. More importantly, expression levels of miR-197 are inversely correlated with PD-L1 expression (n=177; p=0.026) and are associated with worse overall survival (p=0.015). Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.Molecular Therapy (2015); doi:10.1038/mt.2015.10.
Introduction: Therapies targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) have been successful in a subset of patients with non-small-cell lung cancer (NSCLC). PD-L1 expression in tumor tissues has been suggested as a predictive and prognostic marker. We examined the change in PD-L1 expression after gefitinib in patients with EGFR-mutant NSCLC. Materials and methods: Paired tumor tissues were collected before and after gefitinib from 18 patients. PD-L1 expression on the tumor and immune cells was defined by the H-score of immunohistochemical staining (range, 0-300). The correlations between the change in PD-L1 expression and clinicopathologic characteristics were analyzed. Results: PD-L1 expression on tumor cells showed an increase in the median H-score from 25 to 40 (P = .067). Of the 18 patients, 7 (38.9%) had a marked increase in the median H-score (range, 80-180; group A) and 11 (61.1%) had no change in the median H-score (0 for both scores; group B). In groups A and B, the median progression-free survival for gefitinib was 13 and 12 months (P = .594), and the median overall survival was "not reached" and 38 months (P = .073), respectively. MET positivity by immunohistochemistry in biopsies after gefitinib therapy was significantly associated with group A (P = .028). The PD-L1 H-score by immunohistochemistry, but not by tumor cells, showed correlations with other immune cells; FOXP3(+) expression in biopsies before gefitinib use, and PD-1(+) and CD3(+) in biopsies after gefitinib therapy, respectively. Conclusion: PD-L1 expression in tumor cells markedly increased in a subset of patients after gefitinib treatment. Thus, rebiopsy should be considered when using PD-L1 expression as a biomarker.
To analyze the stress distribution on the PDL of the maxillary first molar in a mixed dentition Class III malocclusion, using a Hyrax-type appliance and maxillary protraction. A Class III malocclusion in the mixed dentition was reconstructed based on CBCT images. The 3D FEM comprised the maxilla, alveolar bone, right first permanent molar teeth, and PDL and consisted of 1 133 497 nodes and 573 726 elements. Maxillary protraction force was applied to a hook positioned close to the deciduous canines with 600 g and at 15°, 30°, and 45° downward angles to the maxillary occlusal plane. Analysis was carried out from the top and buccal view of the sagittal plane. The magnitude of the stresses at 15°, 30°, and 45° of protraction angulation resulted in the highest stress magnitude being in the region between the distobuccal and palatal roots, as well as on the distal surface of the mesial root. The vector direction in this area showed traction and mesial movement. With 30° and 45° protraction angulations, the stress was located only between the distobuccal and palatal roots, and the vector direction was more extrusive at 15°. The suggested orthodontic movement is in the mesial direction with a small amount of extrusion with 15° angulation and greater extrusion with 30° and 45°. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Tumors exploit immunoregulatory checkpoints to attenuate T cell responses as a means of circumventing immunologic rejection. By activating the inhibitory costimulatory pathway of Programmed Death 1 (PD1)/PDL1 which provides tumor cells an escape mechanism from immune surveillance, Programmed Death Ligand1 (PDL1)(+) tumors hamper activated tumor-specific T cell functions and render them functionally exhausted. To overcome the inhibitory costimulatory effects of PDL1 on the adoptively transferred T cells, we sought to convert PD1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with CD28 and 4-1BB signaling domains (PD1-CD28-4-1BB, PD1-ACR), anticipating the genetically modified effector T lymphocytes expressing PD1-ACR would exhibit enhanced functional attributes. And the results showed that PD1-ACR expressed T cells retained the ability to bind PDL1, resulting in T cell activation as evidenced by the elevated activity of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), the augmentation of cytokine secretion and the increased proliferative capacity. Moreover, when systemically administered in the mouse model of glioblastoma metastases, PD1-ACR T cells localized at the area of U87 invasive tumor, which results in suppressed tumor growth and enhanced survival of mice with established U87 glioblastoma. Together, these data demonstrated that PD1-ACR has a high potential to serve as a novel strategy to overcome PDL1 mediated immunosuppression of T cells for cancer therapy.
The immune suppressive molecule programmed death-1 (PD-1) is upregulated in activated T lymphocytes and inhibits T-cell function upon binding to its ligands B7-H1 (PD-L1, CD274) and B7-DC (PD-L2, CD273). Substantial experimental data from in vitro cell culture systems and animal models, and more recently from clinical trials, indicate that PD-1/PD-1-ligand interactions are a major mechanism of immune suppression within the tumor microenvironment. Initial clinical studies of antibodies directed against PD-1 and B7-H1 showed both an encouraging safety profile and remarkable antitumor activity in subsets of patients with metastatic disease, including malignancies-such as lung cancer-which were previously thought to be unresponsive to immunotherapy. Preliminary data have suggested a correlation between tumor membrane B7-H1 expression and clinical response to anti-PD-1 antibodies. Several key challenges remain to optimize development of PD-1/B7-H1 pathway blockade, including defining the biologic significance of all potential ligand-receptor interactions in the tumor microenvironment, developing more accurate predictive biomarkers of response, determining the breadth of activity in human malignancies, and developing rational combinations of therapy that address key mechanisms involved in positive and negative regulation of antitumor immune responses. Clin Cancer Res; 19(5); 1021-34. (C) 2013 AACR.
Background: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma. Methods: In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. Results: Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. Conclusions: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; number, NCT01592370.).