Hindawi

Journal of Immunology Research

Volume 2020, Article ID 5825401, 13 pages
https://doi.org/10.1155/2020/5825401

Review Article
Cancer Vaccines: Toward the Next Breakthrough in
Cancer Immunotherapy

1
Yuka Igarashi and Tetsuro Sasada1,2
1
Kanagawa Cancer Center, Research Institute, Division of Cancer Immunotherapy, Japan
2
Kanagawa Cancer Center, Cancer Vaccine and Immunotherapy Center, Japan

Correspondence should be addressed to Yuka Igarashi; [email protected]

Received 22 July 2020; Revised 26 September 2020; Accepted 30 September 2020; Published 17 November 2020

Academic Editor: Fabiano Carvalho

Copyright © 2020 Yuka Igarashi and Tetsuro Sasada. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work
is properly cited.

Until now, three types of well-recognized cancer treatments have been developed, i.e., surgery, chemotherapy, and radiotherapy;
these either remove or directly attack the cancer cells. These treatments can cure cancer at earlier stages but are frequently
ineffective for treating cancer in the advanced or recurrent stages. Basic and clinical research on the tumor microenvironment,
which consists of cancerous, stromal, and immune cells, demonstrates the critical role of antitumor immunity in cancer
development and progression. Cancer immunotherapies have been proposed as the fourth cancer treatment. In particular,
clinical application of immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1/PD-L1 antibodies, in various cancer
types represents a major breakthrough in cancer therapy. Nevertheless, accumulating data regarding immune checkpoint
inhibitors demonstrate that these are not always effective but are instead only effective in limited cancer populations. Indeed,
several issues remain to be solved to improve their clinical efficacy; these include low cancer cell antigenicity and poor
infiltration and/or accumulation of immune cells in the cancer microenvironment. Therefore, to accelerate the further
development of cancer immunotherapies, more studies are necessary. In this review, we will summarize the current status of
cancer immunotherapies, especially cancer vaccines, and discuss the potential problems and solutions for the next breakthrough
in cancer immunotherapy.

1. Introduction Additionally, the World Health Organization (WHO) rec-

ommends the administration of free mumps and varicella
When one hears the word “vaccine,” many people think of vaccines in developed countries, where vaccines are recog-
vaccines against infectious agents, such as viruses and bacte- nized as being among the most versatile and important
ria. For many years, such vaccines have protected human- preventive measures [4].
kind from catastrophic infections [1]. The mechanism The immune system is directed at maintaining homeo-
through which vaccines provide protection against an infec- stasis in living organisms by monitoring the invasion of
tion involves the artificial induction of immune responses foreign pathogens (and associated factors), as well as the
against infectious antigens by inoculating a healthy person presence of abnormal or transformed cells, for their exclu-
with attenuated/detoxified bacteria, viruses, or extracted sion. This process is called immune surveillance [5]. In daily
toxins [2]. The aim of a vaccine is to prevent or reduce the life, humans are exposed to external factors, such as bacteria,
severity of life-threatening infectious diseases (prophylactic viruses, or harmful substances. Additionally, humans are
vaccines). Acquisition of immune memory from vaccines is exposed to various factors that lead to abnormalities and
often effective over long periods of time [3]. A global system transformations in normal cells. However, it is rare that these
of routine immunization against highly prevalent infections exposures or transformations immediately lead to the devel-
has been effectively established; this has resulted in multiple opment of disease, because humans are strongly protected by
individuals developing immunity against various diseases. their immune systems. When there is an imbalance between
2 Journal of Immunology Research

extraneous stimuli and biological defense and when compo- 3. Immunological Characteristics of Cancers
nents of the immune system are unable to eliminate the path-
ogen or malfunctioning cells, conditions, such as infections Progress in the latter half of the 20th century in tumor immu-
and cancers, develop [6]. nology and molecular biology has been remarkable. Numer-
ous studies have vigorously investigated the mechanism by
which tumors evade the immune system. These efforts have
2. History of Cancer Vaccines identified a mechanism called “cancer immunoediting” as
one of the immune evasion tactics utilized by the tumors
Till now, chemotherapy, radiotherapy, and surgical exci- [16]. Cancer immunoediting appears to be the consequence
sion are the three major cancer treatment methods that of antitumor immune responses mediated by antigen recog-
directly remove or target the cancer cells. In addition, nition in the tumor environment. The interaction between
immunotherapies for the treatment of cancer by leveraging the immune system and cancer cells, which originally con-
the innate and/or adaptive immune function in humans tained specific genetic mutations, may cause a selective and
have been extensively studied. The critical role of the biased proliferation of the clones that have lost these muta-
tumor microenvironment (TME), which consists of cancer, tions, leading to tumor escape from the immune system.
stromal, and immune cells that interact with each other, is For these cancers, the immune system might not discrimi-
becoming increasingly apparent. Therefore, cancer immu- nate cancer cells that have lost specific antigens from normal
notherapies have been reconsidered and recognized as host cells, resulting in the possibility that cancer cells do not
the fourth treatment method (Figure 1) [7–9]. Preventive elicit a strong exclusionary immune response.
and therapeutic vaccines exist as representative strategies Additionally, the presentation of cancer cell antigens to
for cancer immunotherapy. The former is aimed at induc- the T cells differs from the presentation of antigens by mature
ing immune memory by administering vaccines to healthy antigen-presenting cells (APCs) in the context of the partici-
persons to prevent morbidity due to a particular cancer. pation of costimulatory molecules. Antigen presentation by
The latter is administered to patients with cancer for dis- the APCs involves the presence of a simultaneous second sig-
ease management by reinforcing or reactivating the nal from costimulatory molecules, such as CD28, for induc-
patient’s own immune system. ing T cell activation during antigen recognition. This
Clinical application of cancer vaccines has faced extreme second signal controls the subsequent T cell response [17].
hurdles despite multiyear research and development efforts When the antigen is presented to T cells without the second
by many researchers. The administration of streptococcal signal, antigen stimulation itself might be ignored; this is
organisms (Coley’s toxin) as a therapeutic vaccine in patients termed unresponsive anergy resulting in the loss of the
with sarcoma in the 1890s by Dr. William B. Coley was the antigen-specific T cell responses. Because cancer cells lack
first report of cancer immunotherapy [10]. In this strategy, such critical second signals, they may not efficiently induce
for both prophylactic and therapeutic purposes, specific T cell responses, even if strong cancer-specific antigens
immune responses were induced against certain sarcoma derived from genetic mutations are presented to T cells.
antigens. The development of this cancer vaccine was based Immunosuppressive cells (e.g., myeloid-derived suppres-
on the clinical findings that the incidence of cancer was low sor cells (MDSCs) and regulatory T (Treg) cells) are recruited
in patients with certain infectious diseases. This phenome- to the TME by chemotactic factors derived from tumor, stro-
non may reflect the fact that infection and inflammation mal, or other immune cells and convey negative signals to the
induce the exposure of antigens abnormally expressed by antitumor immune cells via the expression of inhibitory
cancer cells. It might also be a secondary effect, where the ligands (e.g., programmed death-ligand 1 (PD-L1)) and the
immunological memory acquired from past infection or secretion of immunosuppressive factors (e.g., interleukin 10
inflammation affects the cancer cells. Similarly, antibodies (IL-10), transforming growth factor-beta (TGF-b), and pros-
against abnormal cell surface-associated mucin (MUC1) pro- taglandin E2 (PGE 2)). In doing so, an environment favoring
duced during mumps infection decreases the incidence of cancer cell growth is created [18].
ovarian cancer [11]. Moreover, Bacillus Calmette-Guerin
has been used as a tuberculosis vaccine for a long time [12, 4. Current Status of Cancer Vaccines
13] and is now also widely employed as a therapeutic vaccine
against bladder cancer. The identification of the mechanisms used by the cancer cells
As some types of cancers are caused by infectious viruses, to evade the immune system has resulted in the development
prophylactic vaccines against viral infection can prevent can- of several tools including antibodies, peptides, proteins,
cer development [14, 15]. The Food and Drug Administra- nucleic acids, and immunocompetent cells (dendritic cells,
tion (FDA) has approved two types of prophylactic cancer T cells, etc.) for cancer immunotherapy. With respect to can-
vaccines for targeting the human papillomavirus (HPV) cer vaccines, these techniques fall into three major categories
and hepatitis B virus (HBV) to prevent HPV-related cancers based on format and content, i.e., cell vaccines (tumor or
and HBV-related hepatocarcinoma. However, only a few immune cells), protein/peptide vaccines, and nucleic acid
types of cancer are caused by viral infections. In addition, vaccines (DNA, RNA, or viral vector).
the global vaccination rate for these prophylactic vaccines is
not high. Thus, the number of patients in whom the antiviral 4.1. Cell Vaccines (Tumor Cell Vaccines or Dendritic Cell (DC)
vaccines have successfully prevented cancers is limited. Vaccines). An autologous tumor cell vaccine using a patient’s
Journal of Immunology Research 3

F
Chemotherapy
s
od Cl
et h
lm H
na O
N O HN
io y
e nt N
rap
nv HN he
co F dt
ete
O N
e
re t arg CTLA4
Th Radiotherapy O N ly PD-1
lar
C O
H3

l ec u PDL-1, etc.
P Mo
12C

Immune checkpoint inhibitor

(antibody reagent)
Surgery

Adaptive cell transfer

(NK, NKT, 𝛾𝛿T, TIL, etc)

Engineered T cell therapy

Vaccine (CAR-T, TCR-T)
(cell vaccine (tumor-cell, immune-cell),
Protein/peptide vaccine,
nucleic acid vaccine)

Fourth methods

Immunotherapy

Figure 1: Cancer treatment methods. Conventional methods for cancer treatment include surgery, chemotherapy, and radiation therapy,
which remove or directly attack the cancer cells. Recent advances in medical science have resulted in the addition of cancer
immunotherapies as a fourth treatment method, which can indirectly attack cancers by regulating the patient’s immunity.

own cancer cells is one of the vaccine strategies being evaluated. associated with the individualization of autologous tumor
In this approach, irradiated tumor cells are administered along vaccines. These vaccines have been studied in prostate [43,
with an adjuvant. As this vaccine uses tumor cells, it might be 44], breast [45], and pancreatic cancers [46]. Although
possible to induce T cells specific to any antigen expressed by homologous GVAX against metastatic castration-resistant
the used cells. However, the limitation of this strategy is that a prostate cancer (CRPC) did not achieve its phase 3 clinical
sufficient number of cells is sometimes difficult to obtain [19– trial goals, a combination strategy using allogeneic GVAX
22]. This approach has been attempted in many tumors, includ- against CRPC and an immune checkpoint inhibitor is being
ing lung cancer [22–24], colorectal cancer [20, 25–27], mela- studied [47, 48].
noma [28–30], renal cell carcinoma [31–33], and prostate A new therapeutic approach focuses on DCs that present
cancer [19, 34]. In many cases, tumor cells are genetically mod- antigens to T cells and promote immune system activation.
ified to add functions, such as cytokine production (e.g., IL-2 DC therapy has been intensively studied since the late
[35] and granulocyte-macrophage colony-stimulating factor 1990s [49], when Dr. Ralph M. Steinman, who discovered
(GM-CSF) [36–39]) and costimulation (e.g., B7-1) [32]. GVAX DCs, recognized their potential, and the possibility of using
is a cancer vaccine based on tumor cells genetically modified to DCs as a vaccine [50]. A variety of antigens, including tumor
secrete GM-CSF. It is used after cancer irradiation to stop the cells, tumor-derived proteins or peptides, and DNA/RNA/-
uncontrollable growth of cancer cells. There are two types of virus, could be potentially loaded on DCs. There are addi-
GVAX vaccine approaches, one using autologous cells tional methods, such as the fusion of DCs with tumor cells.
(patient-specific), and the other using allogeneic cells (non- Several receptor types are expressed on the surface of DCs.
patient-specific). GVAX phase 1/2 clinical trials in patients with For example, binding of an antigen to a lectin-like receptor
non-small-cell lung carcinoma have shown good results, corre- known as scavenger receptor on DCs is reported to induce
lating GM-CSF secretion and patient prognosis [40]. However, antigen-specific suppressive CD4(+) T cells. It is noteworthy
no effects have been seen in phase 3 clinical trials for prostate that not all antigen presentation by DCs contributes to
cancer [41]. Currently, several phase 2 trials of GVAX therapy immune activation [51].
for advanced pancreatic cancer have been conducted in combi- In 2010, Provenge (sipuleucel-T; Dendreon Corporation)
nation with body radiation or mesothelin-expressing Listeria was approved by the FDA as a prostate cancer vaccine and
monocytogenes vaccine or cyclophosphamide (CY), with prom- has drawn attention to the use of autologous immune cells
ising results. for immunotherapy. It is a crude leukocyte fraction recovered
An allogeneic tumor cell vaccine that includes tumor cell from the peripheral blood of an individual patient, which is
lines, such as Canvaxin [42], may overcome the limitation then cultured with a prostate carcinoma antigen (prostatic
4 Journal of Immunology Research

acid phosphatase (PAP)) in the presence of GM-CSF. DCs nostimulatory adjuvant has been developed to improve the
are the main active components of Provenge (about 11.2% responsiveness to peptide vaccines [65–68].
[52]) and display the PAP antigen to artificially stimulate
and induce antigen-specific T cells in patients. Provenge is 4.3. Nucleic Acid Vaccines (DNA, RNA, or Viral Vector).
a good example of the complexity of personalized medicine, Nucleic acid (DNA/RNA) vaccines have advantages in that
as personalized cancer vaccines can be effectively created they can simultaneously activate immunity against multiple
using this approach. Nevertheless, all of the processes epitopes [69]. Further, these vaccines are inexpensive and
involved in the production of a personalized vaccine, from can be synthesized stably. When an immunogenic viral vec-
sample collection to transporting, processing, shipping, and tor is used, the adjuvants are not as important, unlike in pep-
administration of the cells, need to be customized for each tide vaccines. However, when a viral vector is not used,
patient, leading to increased labor and cost. developing an efficient delivery method becomes an impor-
tant issue, especially as the efficiency of nucleic acid uptake
4.2. Protein/Peptide Vaccines. Protein/peptide vaccines can into cells might be low [70].
induce immunity against specific antigenic epitopes derived DNA vaccines have shown promise in several prelimi-
from the vaccinated protein/peptides that are expressed in nary studies [71, 72]. For example, VGX3100, a DNA vaccine
cancer cells (and preferably not expressed in normal tissues). for cervical cancer, is in phase 3 clinical trials
When an artificially synthesized antigen protein/peptide is (NCT03185013) [73]. RNA vaccines, unlike DNA vaccines,
administered, it is taken up by professional APCs and pre- are not incorporated into the genome, thereby preventing
sented in complex with the HLA molecules on the cell sur- carcinogenicity. Additionally, unlike DNA vaccines that need
face. When T cells recognize the antigens, cancer-specific to enter the nucleus, RNA vaccines can function in the cyto-
immune responses are induced. Antigenic epitopes derived plasm. Therefore, clearance is quick and the possibility of
from tumor-associated antigens (TAAs) capable of binding causing side effects might be low. RNA is more easily
HLA have been extensively identified. In addition, antigens degraded than DNA, but stability can be enhanced by various
derived from cancer-specific gene mutations that are not modifications, such as formulations with liposomes or stabi-
present in normal tissues have recently attracted attention lizing adjuvants [74–77]. Techniques have also been devel-
as neoantigens. To efficiently search for these neoantigens, oped to stabilize the RNA molecule itself (5 ′ cap structure,
algorithm-based computer searches are rapidly being devel- untranslated regions, and codon usage in translated regions)
oped [53–55]. [78]. Phase 1/2 studies are ongoing for melanoma and kidney
As many early protein/peptide vaccine clinical trials have cancer [79–81]. A phase I study of liposome-encapsulated
resulted in favorable results, phase 3 trials have been con- mRNA for patients with advanced melanoma is also under-
ducted to confirm the results. Unfortunately, most of these way [82]. Further development of nucleic acid delivery
trials have failed, suggesting that single-protein/peptide vac- methods will serve as a breakthrough in nucleic acid vaccines.
cines do not exert sufficient antitumor effects [56]. Even if Viral vectors are used to efficiently carry nucleic acids for
T cell responses were induced by protein-/peptide-derived vaccines. Adjuvants are not required for viral vectors, which
epitopes, the antitumor effects can rarely be achieved with can activate innate immunity and also induce immune
low response rate (less than 10%) [57, 58]. These unexpected responses to viruses. Commonly used viral vectors are derived
results may be explained by several factors, including tumor from poxvirus, vaccinia virus, adenovirus, and alphavirus and
immune escape mechanisms and immunosuppressive TMEs are attenuated or replication-defective for safety. For example,
[59]. some modified vaccinia virus Ankara (MVA) vector-based
There may be problems with the vaccine formulations; vaccines are used to target the renal cell carcinoma 5T4 and
most peptide vaccines developed thus far consist of short- MUC1 antigens [83, 84]. Recombinant adenoviruses are com-
chain peptides (SPs) restricted to MHC class I. Unlike long- monly used in cancer gene therapy because they can transduce
chain peptides (LPs), SPs are able to bind to any cells without dividing and nondividing cells and are easy to produce ([85–
processing and might induce anergy if presented to CD8 T 87], NCT00583024, NCT00197522). Herpes simplex virus
cells without the secondary costimulatory signal [60, 61]. In type 1 (HSV-1), an enveloped dsDNA virus, is used as an
these situations, immune tolerance is induced, creating an oncolytic virus. HSV-1 expressing GM-CSF (e.g., OncoV-
environment favorable for cancer progression. Furthermore, EXGM-CSF) is useful in melanoma [88, 89]. The disadvantage
MHC class I-restricted SPs cannot contribute to the activa- of viral vectors is that repeated administration might be diffi-
tion of MHC class II-restricted helper T cells, which are cult due to the induction of antiviral immune responses. For
important for efficient cytotoxic T lymphocyte (CTL) induc- this reason, a heterologous prime-boost strategy is developing.
tion. However, LPs can be processed to both MHC class I- or For example, PROSTVAC, a vaccine consisting of two poxvi-
class II-restricted antigens and presented by professional rus vectors that express tumor-associated antigen prostate-
APCs, but not by other cell types. Professional APCs that specific antigen (PSA) combined with 3 immune-enhancing
present LP-derived antigens can activate CTL or helper T costimulatory molecules collectively designated as TRICOM
cells without inducing anergy by transmitting signals via (LFA-3, ICAM-1, and B7.1), is under development by Bavar-
both T cell receptors (TCRs) and costimulatory molecules ian Nordic (Denmark) to stimulate an immune response in
[60, 62–64]. Currently, the development of LP vaccines that prostate cancer [90–92]. The results of the PROSTVAC-
contain epitopes for both CTL and helper T cells is being VF/TRICOM phase 3 trial were not as expected, but this vac-
actively pursued. In addition, a novel method with an immu- cine shows promise when combined with immune checkpoint
Journal of Immunology Research 5

inhibitors (NCT02933255, NCT02506114). In addition to approach. For TIL therapy, T cells that recognize cancer-
viruses, bacteria and yeasts are also attracting attention as specific antigens are collected from tumor tissues in patients
new vaccine carriers [93, 94]. with cancer, artificially reactivated by using T cell-
stimulating agents, such as a high IL-2 concentration, and
4.4. Combination Therapy with Cancer Vaccines. Until are then returned to the patients. This approach is potentially
recently, monotherapies using cancer vaccines often had min- simple because genetic modifications are not required, but
imal clinical effects except for certain specific cancer types. the clinical effects might be dependent on the amount and
The relatively low efficacy of monotherapies was attributed quality of infiltrating lymphocytes collected from tumor tis-
to the multifaceted immune evasion mechanisms of cancer, sues. Dudley et al. [103] have reported much information
which are difficult to control by either cancer vaccine alone. on TIL therapy in patients with cancer. Many researchers
As described earlier, the immunosuppressive TME [95] may and doctors are fascinated by their reports on the potential
override any antitumor effects elicited by the cancer vaccine. of TIL therapy in melanoma [104–106]. In the latest method,
In accordance with the development of various immuno- IL-2 and TILs are simultaneously administered to patients to
therapy types, more attention has focused on combination enhance clinical effects [107–109]. In addition, the same
therapies. Several different approaches, including conven- group has conducted similar TIL studies for advanced cervi-
tional chemotherapy/radiation therapy or the latest antibody cal cancer with potential success [110].
therapies [96, 97], have been attempted in combination
either simultaneously or in sequence with immunotherapies. 5.2. TCR/CAR-T Cell Therapy. The availability and perfor-
mance of TIL therapy might be dependent on whether suffi-
4.5. Issues in the Clinical Development of Cancer Vaccines. cient numbers of high-quality antigen-responsive T cells can
During the development of many conventional cancer vac- be secured from tumor tissues in individual patients. To cir-
cines for clinical use, the test designs may have been flawed. cumvent such limitations, peripheral blood mononuclear
For example, clinical effects of cancer vaccines were often cell- (PBMC-) derived lymphocytes, which artificially express
evaluated in patients with a terminal diagnosis whose a desired TCR or chimeric antigen receptor (CAR), have
immune conditions were already substantially compromised been devised and clinically applied as a novel T cell therapy.
by exposure to several other treatments, such as surgery and TCR-T therapy is a therapeutic method using T cells trans-
chemotherapy/radiotherapy, or by progression of the disease. duced with antigen-specific TCRs [111]. CAR-T therapy is
In addition, it is essential to develop accompanying tech- a method of administering T cells with a CAR gene, which
nologies such as adjuvants, manufacturing, and delivery is composed of a fragment derived from a cancer antigen-
methods to employ vaccines and to obtain expected results recognizing antibody gene, gene fragments from intracellular
in clinical settings [98, 99]. The introduction of such state- TCR domains, and other T cell costimulatory molecules.
of-the-art technology may create additional hurdles due to CAR-T therapy is extremely effective in blood cancers
current drug regulations, which are controlled by regulatory [112]. In 2017, the FDA approved CD19 CAR-T therapy
authorities in individual countries, including the FDA, Euro- for B cell acute lymphoblastic leukemia (ALL) which has
pean Medicines Agency (EMA), and Ministry of Health, become refractory to first-line treatment or has recurred
Welfare, and Labour in Japan [100, 101]. These hurdles are more than once [113, 114]. Although CAR-T therapy is
especially important in the development of drugs related to highly effective, the issues surrounding the cost of care with
cancer immunotherapy, where it can be difficult to set up a CAR-T therapy (more than $500,000 for one administration)
primary endpoint to evaluate the effectiveness of a therapy. have yet to be resolved. Notably, CAR-T is effective when a
Thus far, some cytotoxic drugs under investigation have been tumor antigen is monolithic or tumor tissue heterogeneity
known to generally prolong disease-free survival (DFS), but is low (e.g., a genetically uniform tumor, which is often the
not overall survival (OS), but drugs that extend OS without case with blood tumors). However, the efficacy of CAR-T
improving DFS are not very common. Nevertheless, regard- therapy to solid tumors remains limited, because these
ing immunotherapy approaches, a situation often arises tumors generally show more heterogeneity [115].
where OS is extended even if tumor reduction is not observed Another problem with TCR/CAR-T cell therapy in solid
[102]. In addition, as the immune status of individual tumors is the suppressive TME, which inhibits effective infil-
patients may be affected by various factors such as age and tration and/or accumulation of administered T cells inside
past treatment history, it is difficult to adequately predict the tumors. Therefore, a method for effectively driving infil-
the antitumor effects in nonclinical studies. tration of the genetically modified cells into the TME remains
out of reach. Moreover, since target antigens are not uni-
5. The Current Status of Other formly expressed in solid tumors and are different depending
Cancer Immunotherapies on the cancer type, stage, and patient, current TCR/CAR-T
cell therapy is not widely used in patients with cancer. Fur-
In addition to cancer vaccines, other types of cancer immu- thermore, commonly available target antigens similar to
notherapies are in development. These have been described CD19 in blood cancers remain to be identified in solid can-
below. cers [116].

5.1. Tumor-Infiltrating Lymphocyte (TIL) Therapy. When 5.3. Immune Checkpoint Inhibitors. In the 1990s, immune
tumor tissues are available, TIL therapy is a promising checkpoint molecules, including cytotoxic T-lymphocyte-
6 Journal of Immunology Research

Table 1: A list of currently approved cancer immunotherapies.

FDA/EMA MHLW (Japan)

Melanoma Melanoma
non-small cell lung cancer non-small cell lung cancer
renal cell carcinoma renal cell carcinoma
Hodgkin's lymphoma Hodgkin's lymphoma
Nivolumab (Anti-PD-1 Ab) Head neck cancer Head neck cancer
MSI-H/dMMR colorectal cancer gastric cancer
hepatocellular carcinoma diffuse malignant pleural mesothelioma
small cell lung cancer Esophageal cancer
MSI-high colorectal cancer
Melanoma Melanoma
non-small cell lung cancer non-small cell lung cancer
Head neck cancer Urothelial cancer
Hodgkin's lymphoma MSI-high solid tumor
Urothelial cancer renal cell carcinoma ∗ (combination)
MSI-high colorectal cancer Head neck cancer ∗∗ (mono/combination)
Pembrolizumab (Anti-PD-1 Ab) MSI-high cancer
gastric cancer
cervical cancer
hepatocellular carcinoma
Merkel cell carcinoma
renal cell carcinoma
endometrial cancer
Merkel cell carcinoma Merkel cell carcinoma
Avelmab (Anti-PD-L1 Ab) renal cell carcinoma renal cell carcinoma ∗ (combination)
Urothelial cancer
Urothelial cancer non-small cell lung cancer
non-small cell lung cancer extensive-disease small cell lung cancer.
Atezolizumab (Anti-PD-L1 Ab)
breast cencer triple negative breast cancer
small cell lung cancer
Urothelial cancer non-small cell lung cancer (stage 3)
Durvalumab (Anti-PD-L1 Ab)
non-small cell lung cancer
Melanoma Melanoma ∗∗∗ (mono/combination)
Ipilimumab (Anti-CTLA4 Ab) renal cell carcinoma renal cell carcinoma ∗∗∗∗ (combination)
MSI-H/dMMR colorectal cancer
B-ALL (<25 yars-old) B-ALL (<25 yars-old)
Kymriah (CAR-T)
DLBCL (Hodgkin's lymphoma)
Yescarta (CAR-T) DLBCL (Hodgkin's lymphoma) not approved
Sipuleucel-T (Provenge) (DC-vaccine) Prostate cancer not approved
∗ ∗∗ ∗∗∗
Combination with axitinib, monotherapy or combination with chemotherapy, monotherapy or combination with nivolumab, ∗∗∗∗ combination with
nivolumab. MSI-H/dMMR: microsatellite instability-high/deficient mismatch repair; B-ALL: B cell acute lymphoblastic leukemia; DLBCL: diffuse large B
cell lymphoma; Ab: antibody; PD-1: programmed death-1; PD-L1: programmed death ligand-1; CAR: chimeric antigen receptor; DC: dendritic cell; FDA:
Food and Drug Administration; EMA: European Medicines Agency; MHLW: Ministry of Health, Labour and Welfare.

associated protein 4 (CTLA-4) [117] and programmed death and prevent autoimmune responses. The activity of T cells
1 (PD-1) [118], were discovered. Both molecules suppress T is suppressed by ligands binding to CTLA-4 and PD-1. For
cell activation, which is important for exerting antitumor example, the costimulatory molecule CD80/CD86 expressed
effects. The expression of these molecules increases in pro- on APCs enhances T cell activation by simultaneously bind-
portion to T cell activation, and they function as a defense ing to CD28 on T cells during antigen presentation. In con-
system for organisms to inhibit excessive T cell activation trast, CTLA-4 is induced on activated T cells and inhibits
Journal of Immunology Research 7

Hot tumor
Type A

Cold tumor

Cancer
cell Dendritic
cell

B cell

T cell

Macrophage
(inhibitory)

Tertiary lymphoid
structures (TLS)
Type B

Figure 2: Classification of tumors by immune cell infiltration. Tumor types can be classified by the level of immune cell infiltration into
tumors. “Cold tumor,” characterized by the poor infiltration of immune cells, is reported to be one of the reasons why immune
checkpoint inhibitors are ineffective. Contrastingly, a “hot tumor” is characterized by the abundant infiltration of immunocompetent cells,
showing good responses to immune checkpoint inhibitors. Recently, aggregated infiltration of immune cells, known as the tertiary
lymphoid structure (hot tumor, type B), has gained increasing attention compared to separated infiltration of immune cells (hot tumor,
type A).

the costimulatory signal mediated by CD80/CD86 through approved immune checkpoint inhibitors and their indica-
competition with CD28. Additionally, antigen-stimulated T tions. These immune checkpoint inhibitors often show only
cells express PD-1, which suppresses excessive T cell activa- limited and/or transient efficacy, reflecting the complexities
tion by binding to its ligand, PD-L1 or programmed death- of antitumor immunity [129, 130]. For example, immune
ligand 2 (PD-L2) [119]. Additional constituents of the cancer checkpoint inhibitors are less effective in microsatellite stable
microenvironment, such as DCs [120], macrophages [121], tumors [131]. Such tumors often express only minor genetic
and fibroblasts [122], can also express PD-L1 and/or PD- abnormalities and thus possess little antigenic capacity.
L2, forming an immunosuppressive environment where can- Therefore, these tumors fail to induce cancer antigen-
cer is more prone to progress. specific T cells, resulting in unresponsiveness to immune
In addition to evading the immune system by deleting checkpoint inhibitors. In addition, the immunosuppressive
cell surface molecules required for antigen recognition, can- TME might also affect the clinical effects of immune check-
cer cells can often directly use (e.g., hijack) the immunosup- point inhibitors.
pression system, such as immune checkpoints. Some cancer
cells strongly express ligands for immune checkpoint mole-
cules, such as PD-L1 and PD-L2 [123, 124]. A remarkable 6. Challenges for the Future Development of
antitumor effect can thus be observed in some patients by Cancer Immunotherapies: Requirement of
administering treatments that block inhibitory molecules in Lymphocyte Infiltration/Accumulation
T cells [125, 126]. Once antitumor activity is induced and within Tumors
immune memory is established by immune checkpoint
inhibitors in patients with cancer, their clinical effects should Analysis of the interaction among tumor infiltrating immune
be long-lasting. cells (e.g., DCs, MDSCs, CD4/8T cells, and Tregs), stromal
In 2011, both the FDA and EMA approved anti-CTLA-4 cells, and tumor cells is essential to understand the relation-
antibody treatment (ipilimumab) for patients with mela- ship between the TME and the clinical effects of cancer
noma [127, 128]. Since then, several immune checkpoint immunotherapies. Especially, many clinical trials using can-
inhibitors, anti-PD-1, and anti-PD-L1 antibodies have been cer immunotherapies indicate that TIL abundance in the
approved every year. Table 1 shows several currently tumor is an important prognostic factor [132]. For example,
8 Journal of Immunology Research

the magnitude of lymphocyte infiltration to tumors signifi- develop novel approaches, including cancer vaccines. We
cantly contributes to immune checkpoint inhibitor effective- hope that this review will facilitate the further development
ness [133, 134]. The effectiveness of immune checkpoint of cancer immunotherapies.
inhibitors is high against inflammatory-type tumors (hot
tumors) [135, 136], where immunocompetent cells are suffi- Conflicts of Interest
ciently present. In contrast, in immune desert-type tumors
(cold tumors) with less intratumoral lymphocyte infiltration The authors declare that there is no conflict of interest
[137], immune checkpoint inhibitors are less effective. regarding the publication of this paper.
The difference between these tumor types might depend
on whether the immune responses to tumors are maintained Acknowledgments
or not, suggesting that the recruitment/accumulation of
tumor-specific T cells is the limiting factor for therapeutic This research was supported by JSPS KAKENHI Grant
effects. Treatment could thus be optimized by the develop- Number 19K09110 and AMED under Grant Number
ment of techniques to increase lymphocyte infiltration into JP20ae0101076.
tumors either before or during immunotherapy treatment
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