Cancer immunotherapies targeting the PD-1 signaling pathway
Iwai et al. Journal of Biomedical Science
Cancer immunotherapies targeting the PD-1 signaling pathway
Yoshiko Iwai 0 3
Junzo Hamanishi 0 2
Kenji Chamoto 0 1
Tasuku Honjo 1
0 Equal contributors
1 Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University , Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501 , Japan
2 Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University , 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 , Japan
3 Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health Japan , Kitakyushu-shi, Fukuoka 807-8555 , Japan
Immunotherapy has recently emerged as the fourth pillar of cancer treatment, joining surgery, radiation, and chemotherapy. While early immunotherapies focused on accelerating T-cell activity, current immune-checkpoint inhibitors take the brakes off the anti-tumor immune responses. Successful clinical trials with PD-1 monoclonal antibodies and other immune-checkpoint inhibitors have opened new avenues in cancer immunology. However, the failure of a large subset of cancer patients to respond to these new immunotherapies has led to intensified research on combination therapies and predictive biomarkers. Here we summarize the development of PD-1blockade immunotherapy and current issues in its clinical use.
PD-1; PD-L1; Cancer immunotherapy; Immune checkpoint
Cancer immunotherapy, although controversial for many
years, reached a turning point in 2014. Antibodies that
specifically block PD-1 were approved for melanoma in
2014 and for non-small-cell lung cancer (NSCLC) in
2015 in the United States, European Union, and Japan.
The success of clinical trials with novel drugs targeting
immune-checkpoint molecules such as PD-1 led to a
paradigm shift in cancer treatment. Since a PD-1
blockade targets lymphocytes rather than cancer cells, it has a
long-term therapeutic effect that persists even when
cancers cause mutations. Furthermore, the PD-1
blockade is effective against many types of tumors because it
enhances the anti-tumor activity of cytotoxic T
lymphocytes (CTLs), which recognize various tumor-specific
antigens. Several companies are currently conducting
phase 3 trials for different tumor types, including
renalcell cancer (RCC), bladder cancer, head and neck cancer,
ovarian cancer, and brain cancer. Although PD-1
blockade has dramatically improved the response rate for
several cancers, three questions remain to be answered: 1)
Why do some patients not respond to PD-1 blockade?
2) What is the best combination therapy using PD-1
blockade? 3) What predictive biomarkers can be used to
distinguish responsive and unresponsive patients? Here
we review the development of immunotherapy targeting
the PD-1/PD-L1 signaling pathway and discuss the
issues that still need to be resolved in clinical studies.
History of cancer immunotherapy
The concept of cancer immunotherapy goes back to the
late nineteenth century. In 1891, a young New York
surgeon named William Coley began intra-tumoral
injections of bacterial products and observed tumor
shrinkage in patients with sarcoma [
]. Almost a century
later, the role of dendritic cells and their receptors in
sensing microorganisms in the innate immune system
was discovered [
]. The molecular identification of
cancer antigens created new approaches for effective
immunotherapies . In addition, the importance of IFN-γ
and adaptive immunity in cancer immunosurveillance
was demonstrated in preclinical tumor models using
IFN-γR−/− and RAG2−/− mice [
]. These findings
stimulated research into strategies to induce anti-tumor
responses and led to immunotherapies such as cytokine
therapy, peptide vaccine, dendritic-cell vaccine, and
adoptive T-cell therapy. Most of these therapies were
unsuccessful, and one primary reason was a lack of
understanding of the existence and importance of immune
T-cell activating (accelerator) and inhibitory (brake)
receptors regulate the balance between immune response
and immune tolerance. The activation of naïve T cells
requires both antigen presentation (signal 1) and a
second signal sent through costimulatory receptors such as
CD28 (signal 2) (Fig. 1) [
]. When ligated by B7
molecules such as CD80 (B7-1) or CD86 (B7-2), CD28
coreceptors on T cells deliver a positive costimulatory signal,
whereas CTLA-4 coreceptors deliver a negative
coinhibitory signal. PD-1, like CTLA-4, belongs to the
CD28 family and delivers a negative signal when it
interacts with its ligands, PD-L1 (B7-H1 or CD274) and
PDL2 (B7-DC or CD273), which belong to the B7 family
(Fig. 1) [
T cells have immune checkpoints such as PD-1 and
CTLA-4 to reduce autoimmune responses against
selftissues by overly exuberant immune responses to
infection. While most cancer immunotherapies accelerate
Tcell activity, immune-checkpoint inhibitors release the
immune system’s brakes to unleash anti-tumor immune
Immunoinhibitory mechanism by PD-1
PD-1 was discovered in 1992 (Fig. 2). Ishida et al.
isolated the gene that encodes PD-1 by cDNA subtraction
in apoptosis-induced murine T-cell lines. PD-1 is mainly
expressed on activated CD4+ T cells and CD8+ T cells as
well as on B cells in the periphery [
activation-induced expression of PD-1 suggests that
PD1 regulates late-phase immune responses (effector phase,
memory response, chronic infection, etc.) in the
peripheral tissues, rather than the early induction phase in the
PD-1’s extracellular region consists of a single IgV-like
domain, and its cytoplasmic region contains an
immunoreceptor tyrosine-based inhibitory motif (ITIM)
and an immunoreceptor tyrosine-based switch motif
(ITSM). Upon ligation with its physiological ligand
(PDL1 or PD-L2), PD-1 suppresses T-cell activation by
recruiting SHP-2, which dephosphorylates and
inactivates Zap 70, a major integrator of T-cell receptor
(TCR)-mediated signaling [
]. As a result, PD-1
inhibits the T-cell proliferation and effector functions such
as IFN-γ production and cytotoxic activity.
The promoter region of the Pdcd1 gene has two
transcription-factor binding sites that are critical in
regulating PD-1 expression. In naïve T cells,
TCRmediated calcium influx initiates Pdcd1 transcription by
activating NFATc1, which binds to the 5′-promoter
region of the Pdcd1 gene (at position −1160 relative to the
transcription start site) [
]. On the other hand, in
chronically activated (“exhausted”) T cells, interferon-α
(IFN-α) causes prolonged Pdcd1 transcription by the
binding of the transcription factor IRF9 to the Pdcd1
promoter (at position −1040 relative to the transcription
start site) [
]. In addition, the Pdcd1 promoter region
(located 500–1500 base pairs upstream of the initiation
codon) is demethylated during chronic infection, causing
high PD-1 expression in exhausted CD8+ T cells [
While exhausted CD8+ T cells express high
eomesodermin (EOMES), which is regulated by transcription factor
FoxO1, FoxO1 also binds the Pdcd1 promoter and
enhances PD-1 expression [
PD-1 deficiency and autoimmunity
PD-1’s immunoinhibitory function was elucidated by
characterizing the autoimmune phenotype of
PD-1–deficient mice, in which PD-1 deficiency leads to a loss of
peripheral tolerance and the subsequent development of
autoimmunity (Fig. 2) [
]. PD-1–deficient mice
develop different autoimmune diseases depending on their
APC or Target cell
Immunological co-signal Suppressive
discovery of PD-1
PD-1 KO mouse
discovery of PD-L1
discovery of PD-L2
< PD-1 >
Kyoto Nivolumab trial
The history of PD-1 signal
< PD-L1, PD-L2 >
genetic background: C57BL/6-Pdcd1−/− mice develop
lupus-like arthritis and glomerulonephritis with IgG3
and C3 deposits [
]. BALB/c-Pdcd1−/− mice develop
fetal dilated cardiomyopathy with a concomitant
production of autoantibodies against cardiac troponin I [
]. NOD-Pdcd1−/− mice develop type I diabetes with
extensive destruction of the islets . Furthermore,
PD-1–deficient mice crossed with H-2Ld–specific
2CTCR transgenic mice on the H-2b/d background develop
a chronic and systemic graft-versus-host-like disease
]. These findings indicate that PD-1 negatively
regulates immune responses and is essential for maintaining
Distinct physiological functions of PD-1 and CTLA-4
Although PD-1 and CTLA-4 are both induced on
activated T cells, they are expressed at different stages of the
immune response. CTLA-4 is closely related to CD28,
but binds CD80 and CD86 with a much higher affinity
than does CD28 [
]. CTLA-4 is constitutively expressed
on regulatory T (Treg) cells, and transiently expressed
on activated T cells at the early induction phase after
antigen stimulation [
]. In contrast, PD-1 is expressed
on activated T cells at the late effector phase, and high
and persistent PD-1 expression has been observed on
exhausted CD8+ T cells during chronic viral infection
]. CTLA-4 is continuously internalized by
interactions with the adaptor complex AP2 and is almost
undetectable on the cell surface during T-cell activation;
in contrast, PD-1 lacks an AP2-binding motif, which
may allow its sustained expression on the surface of
activated T cells .
Although both PD-1 and CTLA-4 are immune
checkpoints, they regulate different phases of the
immune response. CTLA-4 blocks early T-cell activation
in the lymphoid organs, whereas PD-1 inhibits
effector T-cell activity at later-stage immune responses
in peripheral tissues and in the tumor
microenvironment. PD-1 and CTLA-4 also have distinct inhibitory
mechanisms. CTLA-4 completely blocks costimulation
by CD28 through its stronger affinity for B7
molecules, whereas PD-1’s inhibitory function depends
mostly on its recruitment of SHP-2 [
differences in expression and inhibitory mechanisms
are probably responsible for the different autoimmune
phenotypes of PD-1 and CTLA-4 deficiency.
CTLA-4deficient mice develop devastating autoimmune
diseases and massive and systemic lymphoproliferation,
and die within 5 weeks of birth . In contrast,
PD1–deficient mice remain relatively healthy into later
stages of life, eventually developing relatively mild,
organ-specific autoimmune symptoms depending on
their genetic background [
]. Consistent with the
phenotypes of PD-1–knockout and CTLA-4–knockout
mice, PD-1 inhibitors are less toxic than CTLA-4
Identification of PD-1 ligands
PD-L1 and PD-L2 were identified as PD-1 ligands in
2000 and 2001, respectively (Fig. 2) [
]. PD-L1 and
PD-L2 are type I transmembrane proteins with IgV- and
IgC-like domains in the extracellular region. PD-L1 is
broadly expressed in both lymphoid and non-lymphoid
tissues. PD-L1 is upregulated upon activation on
hematopoietic cells, especially on antigen-presenting
cells (APCs) such as dendritic cells,
macrophages/monocytes, and B cells [
]. PD-L1 is also expressed on
activated T cells. Importantly, PD-L1 is expressed on
non-lymphoid cells, including parenchymal cells and
vascular endothelial cells in the peripheral tissues, and is
upregulated by IFN-γ and other inflammatory cytokines
secreted by activated T cells [
23, 26, 38
]. The expression
of PD-L1 in peripheral tissues rather than on
professional APCs is crucial for preventing autoimmune
damage to tissues [
]. Interestingly, PD-L1 is expressed in
various tumor cells and virus-infected cells. The
expression of PD-L1 on target cells allows PD-1 to directly
inhibit T-cell effector functions against the target cell.
Unlike PD-L1, which is expressed in many different
tissues, PD-L2 is expressed only on APCs such as dendritic
cells and macrophages [
Regulation of tumor immunity by PD-1
The PD-1/PD-L1 signaling pathway is crucial in
dampening immunosurveillance for tumors. Tumors can
escape host immune surveillance by expressing PD-L1,
which negatively regulates immune responses by
interacting with PD-1 on T cells (Fig. 1) [
]. Indeed, data
from clinical samples indicate that the high expression
of PD-1 ligands on tumors is correlated with a poor
The first evidence of the PD-1/PD-L1 pathway’s
involvement in tumor immunity was found in animal
]. PD-L1 overexpression on P815
mastocytomas was shown to inhibit the cytolytic activity of CD8+
T cells by engaging PD-1 in vitro, and to markedly
enhance tumorigenesis and tumor invasiveness in vivo.
Anti–PD-L1 treatment inhibited the growth of PD-L1–
expressing P815 tumor cells, and of J558L myeloma
cells, which endogenously express PD-L1. Importantly,
no tumors developed in Pdcd1−/− mice after their
inoculation with J558L cells. These results revealed the
effectiveness of the PD-1/PD-L1 blockade for tumor therapy.
Although a CTLA-4 blockade enhances immune
responses against immunogenic tumors such as lymphoma
in animal models, it is not effective as a single agent
against poorly immunogenic tumors such as B16
]. However, even as a single agent, a PD-1
blockade was found to be therapeutic against B16
melanoma in a liver metastasis model [
]. These results
suggested that PD-1 blockade can be successfully applied
to metastatic tumors, and that it has a stronger
therapeutic potential than does CTLA-4 blockade.
Clinical application of the PD-1/PD-L1 blockade
Several clinical studies have reported that PD-L1
overexpression is related to a poor prognosis for several types
of tumors, including renal-cell carcinoma, bladder
cancer, esophageal cancer, pancreatic cancer, gastric cancer,
hepatocellular carcinoma, and ovarian cancer [
]. In ovarian cancer, PD-L1 expression is negatively
correlated with the number of intra-epithelial infiltrating
CD8+ T cells, suggesting that the PD-L1 expression on
tumor cells prevents CD8+ T cells from infiltrating
tumor sites . These studies indicated that blocking
PD-1 signaling might improve clinical outcomes for
patients with these malignancies. In 2006, a
proof-ofconcept clinical study using a PD-1 signal inhibitor
against treatment-resistant solid tumors was initiated in
the United States (Fig. 2) [
A fully humanized monoclonal antibody (mAb) against
PD-1 (nivolumab; also known as ONO4538, MDX-1106,
or BMS-936558) was first developed using genetically
modified mice carrying loci encoding human
immunoglobulins. The IgG4 isotype of nivolumab minimizes
complement activity or antibody-dependent
cellmediated cytotoxicity (ADCC) [
]. This antibody
carries a serine-to-proline substitution at position 228 to
minimize the effect of ADCC against activated T cells.
Clinical trials of nivolumab began in 2006 in the United
States and in 2009 in Japan (Fig. 2). The phase 1 study
of nivolumab showed cumulative response rates of 18%
for NSCLC, 28% for melanoma, and 27% for renal
carcinoma. Grade 3 or 4 drug-related adverse events
occurred in 14% of the patients [
]. Notably, nivolumab
has demonstrated durable clinical activity as a single
agent, with far fewer side effects than are seen with
ipilimumab, a mAb against CTLA-4 [
]. A clinical trial
using anti–PDL1 mAbs (BMS-936559 or MDX-1105)
showed relatively low response rates compared to an
anti–PD-1 mAb .
The PD-1 blockade approach has unique features
compared to standard therapies. Conventional
chemotherapies usually target a particular molecule in the
tumor cells. The tumor cells can escape the therapy with
mutations of the target molecules, leading to rapid
regression. However, a PD-1 blockade is applicable to a
wide range of cancers and provides a response over a
longer period because it activates an anti-tumor immune
system that can target mutated proteins [
addition, PD-1 blockade has a significantly lower rate of
high-grade toxicities than other immunotherapies or
standard therapies, because the anti-tumor immunity
preferentially recognizes tumor-derived antigens, not
self-antigens. In a phase 3 study comparing nivolumab
to the plant alkaloid chemotherapy drug docetaxel in
272 patients with advanced squamous-cell NSCLC, the
response rate was 20% with nivolumab versus 9% with
]. The overall survival rate at 1 year was
42% with nivolumab versus 24% with docetaxel. The
frequency of grade 3 or 4 treatment-related adverse events
was much lower in the nivolumab group (7%) than in
the docetaxel group (55%).
To date, at least 500 clinical studies with PD-1 signal
inhibitors have been conducted with nine types of
antibodies from eight pharmaceutical companies (Table 1
and Fig. 2) on at least 20 types of solid and
hematological malignant tumors (Table 2) [
]. The total
number of subjects worldwide is more than 20,000,
according to a clinical trials database managed by the U.S.
National Institutes of Health (https://clinicaltrials.gov/
[CTG]). The U.S. Food and Drug Administration (FDA)
approved nivolumab for patients with unresectable or
metastatic melanoma in 2014, for NSCLC in 2015, and
for classical Hodgkin’s lymphoma and RCC in 2016. The
FDA also approved pembrolizumab for melanoma in
2014 and for NSCLC in 2015. Atezolizumab, an anti–
PD-L1 antibody, was approved for unresectable bladder
cancer and for NSCLC in 2016.
Regarding clinical trials for ovarian cancer, we first
conducted the principal investigator-initiated two-cohort
(1 or 3 mg/kg, n = 10 each) phase 2 clinical trial of
nivolumab in 20 patients with platinum-resistant recurrent
ovarian cancer at Kyoto University Hospital in 2011
(Fig. 2) (UMIN000005714) [
]. The objective
response rate at 3 mg/kg was 20%; this included two cases
of complete response (CR). For all 20 patients, the
response rate was 15% and the durable CR (DCR) was
45%. The median progression-free survival (PFS) and
overall survival (OS) were 3.5 and 20.0 months,
respectively . In our ongoing follow-up study of this trial, a
durable anti-tumor response with nivolumab has been
observed in two patients with a complete response for
over 1 year. After completing the 1-year nivolumab
treatment, these two patients survived without any
antitumor treatment for over 2 years [
]. Based on this
positive result, we are conducting a large randomized
phase 2 trial with nivolumab versus standard 2nd-line
chemotherapy (NINJA study, JapicCTI-153004). So far,
at least 30 clinical trials have been completed or are
underway for ovarian cancers using the monotherapeutic
anti–PD-1 antibody pembrolizumab (response rate [RR]
10%, n = 104) , the anti–PD-L1 antibody avelumab
(RR 10%, n = 104) [
], or combinations of these agents
with conventional cancer therapies (CTG).
Combination therapy with blockade of PD-1/PD
L1 signal and new co-signals
Patients who respond poorly or are unresponsive to
immunotherapies appear to lack preexisting anti-tumor
TAll antibodies used in clinical trials as of September 1, 2016 were extracted from ClinicalTrials.gov
Abbreviations: U U.S. Food and Drug Administration (FDA) approved; E European Medicines Agency (EMA) approved, J Japanese Pharmaceutical and Medical
Devices Agency (PMDA) approved
DNA mismatch repair deficient
cell responses. One possible approach to overcoming this
issue is to combine the two immune-checkpoint inhibitors
anti–PD-1 and anti–CTLA-4 (Fig. 1). In a phase 1 study
on patients with advanced melanoma, concurrent therapy
with nivolumab and ipilimumab induced rapid and
durable responses, resulting in an unprecedented 2-year
survival rate of over 80%; 53% of the patients had an
objective response with more than 80% tumor reduction
]. However, grade 3 or 4 therapy-related adverse events
occurred in 53% of the patients. In this double-blind
study, 142 patients with metastatic melanoma
randomly received ipilimumab combined with nivolumab
or placebo once every 3 weeks for four doses. The
objective response rate was significantly higher for
patients who received the combined ipilimumab and
nivolumab regimen (60%) compared to those treated
with ipilimumab monotherapy (11%). The median PFS
was 8.9 months with the combination therapy and
4.7 months with ipilimumab alone [
]. Based on this
confirmatory trial, the FDA approved this combined
nivolumab and ipilimumab therapy for unresectable
or metastatic melanoma in 2015. Combined
nivolumab and ipilimumab therapy is now being clinically
applied to other cancer types, including RCC [
], and ovarian cancer (NCT02498600).
However, the frequency of grade 3 or 4
immunerelated adverse events (irAEs) is over 50%, and this
issue remains to be resolved [
Several clinical trials are underway for PD-1 inhibitors
in combination with other immune-checkpoint
inhibitors, immune activators, and chemotherapies (Table 3
and Fig. 1). However, combining immunotherapies with
chemotherapies can increase irAEs. For example,
compared to PD-L1 mAb (durvalumab) or EGFR inhibitor
(osimertinib) monotherapies, combining the two
therapies induced a significantly higher risk of interstitial lung
disease (2% [n = 23 of 1149], 2.8% [35 of 1207], and 38%
[n = 13 of 34], respectively) [
]. At present, at least 20
clinical trials with combined PD-1 inhibitors and focal
radiation therapy and more than five trials combining
anti-PD-1 mAb with chemoradiation therapy are
Biomarkers for predicting the efficacy of the PD
1-blockade cancer immunotherapy
Potential predictive biomarkers for anti-tumor responses
with PD-1 inhibitors can be found among both tumor
cell-related factors and host immunological factors.
Recent reports identified the frequency of genetic
mutations derived from microsatellite instability (MSI) with
DNA mismatch repair deficiency (MMRd) in cancer
cells as a candidate biomarker [
mutated neo-antigens expressed on the surface of cancer
cells are recognized by T cells and B cells as foreign
antigens, either directly or through the APC system.
Cancer cells exposed to IFN-γ released from activated T
cells express PD-L1, thereby establishing an acquired
immune resistance ; in this case, PD-1 signal
inhibitors are more likely to be effective. Thus, genome-wide
mutation analysis (i.e., Mutanome) of cancer cells using
next-generation sequencing technology and diversity
analysis of the T-cell or B-cell repertoire (i.e.,
Immunome) have attracted a lot of attention as strategies for
identifying predictive biomarkers (Fig. 3) [
on this concept, researchers have examined candidate
biomarkers such as the PD-L1 level on tumor cells and
the frequency of tumor-infiltrating lymphocytes [
the levels of IFN-γ–related genes in tumor cells [
the frequency of mutations in tumor cells [
and the diversity of TCRs in tumor antigen–specific T
74, 81, 82
]. However, these candidates do not
always correspond to a high response according to cancer
type. For example, clinical trials of PD-1 inhibitors for
squamous-cell lung cancer and ovarian cancer showed
no correlation between clinical effect and PD-L1
expression on tumor tissues [
57, 60, 64
]. A recent report by
Hugo et al. revealed that high mutational loads and
genes related to T-cell checkpoints, such as CD8A/B,
PD-L1, LAG3, and IFN-γ, in tumor tissues were not
associated with responsiveness in breast cancer patients
]. Interestingly, the breast cancer susceptibility gene
(BRCA) 2 mutation status is associated with
responsiveness to PD-1 mAb therapy [
], while no correlation
was found between BRCA2 and avelumab’s clinical effect
on ovarian cancer [
]. It is urgent to validate current
candidates and to discover new biomarkers for clinical
response to PD-1 signal inhibitors.
Toxicities of PD-1/PD-L1 signal blocking
IrAEs associated with PD-1 blockade therapy include
interstitial pneumonitis, colitis with gastrointestinal
perforation, type 1 diabetes, severe skin reactions, immune
thrombocytopenia, neutropenia and sepsis after
corticosteroid therapy, encephalopathy and neurological
sequelae, Guillain-Barré syndrome, myelitis, myasthenia
gravis, myocarditis and cardiac insufficiency, acute
adrenal insufficiency, and nephritis [
]. Based on
several previous clinical trials, guidelines and specific care
algorithms have been established for the identification,
early intervention, and management of irAEs [
While irAEs can develop at any time, most of the
immune toxicities of nivolumab occur within the first
4 months [
]. The median time to onset of irAEs
tends to differ depending on the type of toxicity, and
can be roughly classified as early (<2 months: skin,
gastrointestinal, or hepatic irAEs) or late (>2 months:
pulmonary, endocrine, and renal-related irAEs). To treat
new types of adverse events and to reduce the frequency
PD-1 mAb (Pembrolizumab) with SBRT
Multi-kinase inhibitor (Sunitinib)
PD-L1 mAb (Durvalumab)
EGFR inhibitor (Osimertinib)
a Tyrosine kinase inhibitor refractory metastatic recal cell cancer
of immunological toxicities, oncologists should form and
collaborate with networks of organ-specific medical
doctors, pharmacists, and nurses.
Basic and translational studies in the 20 years since
PD1’s discovery have demonstrated the concept of immune
surveillance in mice and humans. The recovery of T-cell
anergy by blocking PD-1 signals on T cells yielded
incredible clinical benefits for several types of
malignancies. Nevertheless, there is a still a great deal of
exploratory research needed to clarify the fundamental
mechanism and predictive biomarkers for the efficacy
and adverse effects of this therapeutic strategy. To
advance the development of PD-1 signal inhibitors in
cancer therapy, it is important to continue both
1. Genetic mutation
6. Upregulation of PD-L1
3. Recognizing and presenting neo-epitope
5. IFN- releasing
4. T cell/B cell
activation and expansion
PD-L1/PD-1 signal induces acquired immunosuppression
PD-1 signal inhibitors may be effective ?
Fig. 3 Genomic mutations and PD-1 signal inhibitors. (1) Genetic mutations in cancer cells create neo-antigens. (2) Neo-antigens are expressed on the
surface of the cancer cells. (3) Recognition of a neo-antigen as a foreign body by an APC induces a T-cell response, and (4) consequently activates
T cells and B cells. (5) Activated T cells release IFN-γ. (6) A cancer cell that is exposed to IFN-γ expresses PD-L1, thereby establishing an acquired
immune resistance. In this particular tumor microenvironment, PD-1 signal inhibitors appear to be effective; thus, genome-wide mutation analysis
(i.e., Mutanome) of cancer cells using next-generation sequencing technology and diversity analysis of the T-cell or B-cell repertoire (i.e.,
Immunome) are valuable next strategies for identifying predictive biomarkers [
]. APC, antigen-presenting cell
translational and reverse-translational research
approaches, including molecular and genomic studies to
elucidate the interactions between host and tumor cells.
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IY, HJ, and CK are eaqually contributed. All authors read and approved the
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