Cancer immunology a translational medicine context

Cancer Immunology
A Translational Medicine
Context
Nima Rezaei
Editor
Second Edition

123


Cancer Immunology


Nima Rezaei
Editor

Cancer Immunology
A Translational Medicine Context
Second Edition


Editor
Nima Rezaei
Research Center for Immunodeficiencies
Children’s Medical Center
Pediatrics Center of Excellence
Tehran University of Medical Sciences
Tehran
Iran
Department of Immunology
School of Medicine

Tehran University of Medical Sciences
Tehran
Iran
Network of Immunity in Infection
Malignancy and Autoimmunity (NIIMA)
Universal Scientific Education and Research Network (USERN)
Tehran
Iran

ISBN 978-3-030-30844-5    ISBN 978-3-030-30845-2 (eBook)
/>© Springer Nature Switzerland AG 2020
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This book would not have been possible without the continuous
encouragement by my parents and my wife, Maryam.

I wish to dedicate it to my daughters, Ariana and Arnika,
with the hope that progress in diagnosis and treatment of these
diseases may result in improved survival and quality of life for
the next generations, and at the same time that international
collaboration in research will happen without barriers.
Whatever I have learnt, comes from my mentors. This book is
therefore dedicated also to all of them, but most importantly to
the patients and their families whose continuous support has
guided me during the years.


Preface

The rapid flow of studies in the field of cancer immunology during the last
decade has increased our understanding of the interactions between the
immune system and cancerous cells. In particular, it is now well-known that
such interactions result in the induction of epigenetic changes in cancerous
cells and the selection of less immunogenic clones as well as alterations in
immune responses. Understanding the cross-talk between nascent transformed cells and cells of the immune system has led to the development of
combinatorial immunotherapeutic strategies to combat cancer.
Cancer Immunology series, a three-volume book series, is intended as an
up-to-date, clinically relevant review of cancer immunology and immunotherapy. The first edition of the book was published 4 years ago, which was
very welcomed by the readers, made us to work on the second edition of the
book in such a short period of time.
Volume I, Cancer Immunology: A Translational Medicine Context, is
focused on the immunopathology of cancers. Volume II, Cancer Immunology:
Bench to Bedside Immunotherapy of Cancers, is a translation text explaining
novel approaches in the immunotherapy of cancers; and finally, Volume III,
Cancer Immunology: Cancer Immunotherapy for Organ-Specific Tumors,
thoroughly addresses the immunopathology and immunotherapy of organ-­

specific cancers.
In Volume I, interactions between cancerous cells and various components
of the innate and adaptive immune system are fully described. Notably, the
principal focus is very much on clinical aspects, the aim being to educate
clinicians on the clinical implications of the most recent findings and novel
developments in the field. To meet this purpose, this volume was extended
from 26 chapters in the first edition to 33 chapters in the second edition. After
vii


Preface

viii

an overview on cancer immunology in Chap. 1, the role of innate immunity
in cancers is explained in Chaps. 2 and 3, followed by the adaptive immunity,
including B-cells, T-cells, and T regulatory and Th17 cells in Chaps. 4–8. NK
cells, plasmacytoid dendritic cells, CD95/CD95L signaling pathway, and
MHC class I molecules are separately described in Chaps. 9–12, respectively.
Cytokines and chemokine receptors are explained in Chaps. 13 and 14,
respectively. Chapter 15 focuses on inflammasome in cancer. Cancer immunoediting is a subject that is explained in Chap. 16. Meanwhile, Chaps. 17
and 18 explain apoptosis and autophagy in cancers. Subsequently, Chap. 19
presents the prognostic value of innate and adaptive immunity in cancers.
Immunogenetics and epigenetics are explicated in Chaps. 20–22. In addition,
immunosenescence (Chap. 23), nutrition (Chap. 24), immunodeficiencies
(Chap. 25), and allergies (Chap. 26) are individually described in the following chapters. Chapter 27 enlightens systems biology in cancer immunology,
while immunological diagnostic tests, including immunohistochemistry, fluorescent in situ hybridization, molecular and functional imaging as well as
imaging with radiolabeled monoclonal antibodies are mentioned in Chaps.
28–32. Finally, by allocating the final chapter to flow cytometry in cancer
immunotherapy, Volume I comes to its end.

The Cancer Immunology series is the result of valuable contribution of
more than 300 scientists from more than 100 well-known universities/institutes worldwide. I would like to hereby acknowledge the expertise of all contributors, for generously devoting their time and considerable effort in
preparing their respective chapters. I would also like to express my gratitude
to the Springer Nature publication for providing me the opportunity to publish the book.
Finally, I hope that this translational book will be comprehensible, cogent,
and of special value for researchers and clinicians who wish to extend their
knowledge on cancer immunology.
Tehran, Iran

Nima Rezaei


Acknowledgment

I would like to express my gratitude to the editorial assistants of this book, Dr.
Farnaz Delavari and Dr. Mahsa Keshavarz-Fathi. With no doubt, the book
would not have been completed without their contribution.

ix


Contents

1Introduction on Cancer Immunology and Immunotherapy��������   1
Nima Rezaei, Seyed Hossein Aalaei-Andabili, Neda Amini,
Farnaz Delavari, Mahsa Keshavarz-­Fathi,
and Howard L. Kaufman
2Role of Innate Immunity in Cancers
and Antitumor Response ����������������������������������������������������������������  11
Masahisa Jinushi and Muhammad Baghdadi

3Tumor-Associated Myeloid Cells in Cancer Progression ������������  29
Tamara Gulic, Rita Silva-Gomes, Sadaf Davoudian,
Marina Sironi, Paola Allavena, Alberto Mantovani,
and Barbara Bottazzi
4B-Cells in Cancer Immunology: For or Against
Cancer Growth?������������������������������������������������������������������������������  47
Qiao Li, Qin Pan, Huimin Tao, Xiao-Lian Zhang,
Shiang Huang, and Alfred E. Chang
5The Roles of CD4+ T-Cells in Tumor Immunity ��������������������������  63
Soheil Tavakolpour and Mohammad Darvishi
6Regulatory T-Cells and Th17 Cells in Tumor
Microenvironment����������������������������������������������������������������������������  91
Chang H. Kim
7T-Cell Metabolism and Its Dysfunction Induced by Cancer�������� 107
Heriberto Prado-Garcia, Rosa Sandoval-Martinez,
and Susana Romero-Garcia
8The Role of Exhaustion in Tumor-­Induced
T-Cell Dysfunction in Cancer���������������������������������������������������������� 117
Heriberto Prado-Garcia and Susana Romero-Garcia
9The Role of NK Cells in Cancer������������������������������������������������������ 133
Vladimir Jurišić, Ana Vuletić, Katarina Mirjačić Martinović,
and Gordana Konjević
10Role of Plasmacytoid Dendritic Cells in Cancer �������������������������� 147
Michela Terlizzi, Chiara Colarusso, Aldo Pinto,
and Rosalinda Sorrentino
xi


xii

11The CD95/CD95L Signaling Pathway:
A Role in Carcinogenesis���������������������������������������������������������������� 171
Amélie Fouqué and Patrick Legembre
12MHC Class I Molecules and Cancer Progression:
Lessons Learned from Preclinical Mouse Models������������������������ 189
Irene Romero, Ignacio Algarra, and Angel M. Garcia-Lora
13Role of Cytokines in Tumor Immunity
and Immune Tolerance to Cancer�������������������������������������������������� 205
Lucien P. Garo and Murugaiyan Gopal
14Role of Chemokines and Chemokine Receptors in Cancer �������� 235
Pierre-Louis Loyher, Mathieu Paul Rodero,
Christophe Combadière, and Alexandre Boissonnas
15Role of the Inflammasome in Cancer�������������������������������������������� 263
Michela Terlizzi, Chiara Colarusso, Aldo Pinto,
and Rosalinda Sorrentino
16Cancer Immunoediting: Immunosurveillance,
Immune Equilibrium, and Immune Escape���������������������������������� 291
Alka Bhatia and Yashwant Kumar
17Apoptosis and Cancer���������������������������������������������������������������������� 307
Mei Lan Tan, Shahrul Bariyah Sahul Hamid,
Muhammad Asyraf Abduraman, and Heng Kean Tan
18Endoplasmic Reticulum Stress and Autophagy in Cancer���������� 355
Mei Lan Tan, Heng Kean Tan,
and Tengku Sifzizul Tengku Muhammad
19Prognostic Value of Innate and Adaptive Immunity
in Cancers ���������������������������������������������������������������������������������������� 403
Fabio Grizzi, Elena Monica Borroni, Daniel Yiu,
Floriana Maria Farina, Ferdinando Carlo Maria Cananzi,
and Luigi Laghi
20Immunogenetics of Cancer�������������������������������������������������������������� 417

Armin Hirbod-Mobarakeh, Mahsima Shabani,
Mahsa Keshavarz-Fathi, Farnaz Delavari,
Ali Akbar Amirzargar, Behrouz Nikbin, Anton Kutikhin,
and Nima Rezaei
21Epigenetics and MicroRNAs in Cancer ���������������������������������������� 479
Petra M. Wise, Kishore B. Challagundla, and Muller Fabbri
22The Role of DNA Methylation in Cancer�������������������������������������� 491
Sepideh Shahkarami, Samaneh Zoghi, and Nima Rezaei
23Immunosenescence, Oxidative Stress, and Cancers �������������������� 513
Tamas Fulop, Graham Pawelec, Gilles Dupuis, Rami Kotb,
Bertrand Friguet, Jacek M. Witkowski, and Anis Larbi

Contents


Contents

xiii

24Nutrition, Immunity, and Cancers ������������������������������������������������ 533
Hassan Abolhassani, Niyaz Mohammadzadeh Honarvar,
Terezie T. Mosby, and Maryam Mahmoudi
25Inborn Errors of Immunity and Cancers�������������������������������������� 545
Mona Hedayat, Waleed Al-Herz, Asghar Aghamohammadi,
Kim E. Nichols, and Nima Rezaei
26Allergies and Cancers���������������������������������������������������������������������� 585
Delia Waldenmaier and Axel Lorentz
27Envisioning the Application of Systems Biology
in Cancer Immunology�������������������������������������������������������������������� 599
Tanushree Jaitly, Shailendra K. Gupta, Olaf Wolkenhauer,

Gerold Schuler, and Julio Vera
28Principles of Immunological Diagnostic Tests for Cancers���������� 625
Amber C. Donahue and Yen-lin Peng
29Immunohistochemistry of Cancers������������������������������������������������ 645
Alireza Ghanadan, Issa Jahanzad, and Ata Abbasi
30Fluorescent In Situ Hybridization:
Methods and Application in Cancer Diagnosis ���������������������������� 711
Roxana Karimi-Nejhad and Alireza Ghanadan
31Cancer Molecular and Functional Imaging���������������������������������� 729
Farnaz Najmi Varzaneh and Behnoud Baradaran Noveiry
32Cancer Imaging with Radiolabeled Monoclonal Antibodies ������ 739
Sara Harsini and Nima Rezaei
33Flow Cytometry in Cancer Immunotherapy:
Applications, Quality Assurance, and Future ������������������������������ 761
Cécile Gouttefangeas, Steffen Walter, Marij J. P. Welters,
Christian Ottensmeier, Sjoerd H. van der Burg,
and Cliburn Chan
Index���������������������������������������������������������������������������������������������������������� 785


Abbreviations

γδ T-cells Gamma delta T-cells
ACT
Adoptive cell transfer
AICL
Activation-induced C-type lectin
ALL
Acute lymphoblastic leukemia
AML

Acute myeloid leukemia
APCs
Antigen presenting cells
BAT3
HLA-B-associated transcript 3
BCL-6 Transcription factor B-cell lymphoma 6
CAR
Chimeric antigen receptor
CLL
Chronic lymphocytic leukemia
CML
Chronic myeloid leukemia
CXCR5 CXC chemokine receptor 5
DAMPs Damage-associated molecular patterns
DCs
Dendritic cells
GM-CSF Granulocyte-macrophage colony-stimulating factor
HAHemagglutinins
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HIV
Human immunodeficiency virus
HMGB1 High-mobility group box 1
HN
Hemagglutinin neuraminidases
HVEM Herpesvirus entry mediator
ICOS
Inducible co-stimulator

IFN I
Type I interferon
IFN-γInterferon-gamma
LIGHT Homologous to lymphotoxin exhibits inducible expression and
competes with HSV glycoprotein D for binding to herpesvirus
entry mediator, a receptor expressed on T lymphocytes
MM
Multiple myeloma
NKp44L NKp44 ligand
NKT
Natural killer T
NLR
Nod-like receptors
nTregs
Natural Tregs
PAMPs Pathogen-associated molecular patterns
PBMCs Peripheral blood mononuclear cells
PCNA
Proliferating cell nuclear antigen

xv


xvi

PfEMP1 Plasmodium falciparum erythrocyte membrane protein-1
RCC
Renal cell carcinoma
Tfh
Follicular helper T

ThT-helper
TILs
Tumor-infiltrating lymphocytes
TLR
Toll-like receptors
TNF-α Tumor necrosis factor-alpha
TNM
Tumor, node, and metastasis
Tr1 cells IL-10-producing type 1 Tregs
Treg
Regulatory T-cells

Abbreviations


1

Introduction on Cancer
Immunology and Immunotherapy
Nima Rezaei, Seyed Hossein Aalaei-Andabili,
Neda Amini, Farnaz Delavari, Mahsa Keshavarz-­Fathi,
and Howard L. Kaufman

Contents
1.1

Introduction

 2

1.2

Cancer Immunity

 2

1.3

Cancer and Immune System Impairment

 3

1.4

Immune System Reaction to Cancer

 3

1.5
 enetic and Environmental Carcinogenesis
G
1.5.1 Cancer Cells Escape from Host Immunosurveillance
1.5.2 Cancer Immunodiagnosis

 4
 4
 5

1.6
 ancer Treatment

C
1.6.1 Cancer Immunotherapy
1.6.2 Cancer Cell “Switch”

 5
 5
 6

1.7

Concluding Remarks

 7

References

N. Rezaei (*)
Research Center for Immunodeficiencies,
Children’s Medical Center, Pediatrics Center
of Excellence, Tehran University of Medical
Sciences, Tehran, Iran
Department of Immunology, School of Medicine,
Tehran University of Medical Sciences,
Tehran, Iran
Network of Immunity in Infection, Malignancy and
Autoimmunity (NIIMA), Universal Scientific
Education and Research Network (USERN),
Tehran, Iran
e-mail:
S. H. Aalaei-Andabili

Research Center for Immunodeficiencies,
Children’s Medical Center, Pediatrics Center of
Excellence, Tehran University of Medical
Sciences, Tehran, Iran

 7
Thoracic and Cardiovascular Surgery, Department of
Surgery, College of Medicine, University of Florida,
Gainesville, FL, USA
Cancer Immunology Project (CIP), Universal
Scientific Education and Research Network
(USERN), Gainesville, FL, USA
N. Amini
Department of Surgery, Sinai Hospital,
Baltimore, MD, USA
Department of Surgery, the Johns Hopkins University
School of Medicine, Baltimore, MD, USA
Cancer Immunology Project (CIP), Universal
Scientific Education and Research Network
(USERN), Baltimore, MD, USA
F. Delavari
Interactive Research Education and Training
Association (IRETA), Universal Scientific Education
and Research Network (USERN), Tehran, Iran

© Springer Nature Switzerland AG 2020
N. Rezaei (ed.), Cancer Immunology, />
1

N. Rezaei et al.

2
M. Keshavarz-Fathi
Cancer Immunology Project (CIP), Universal
Scientific Education and Research Network
(USERN), Tehran, Iran
School of Medicine, Tehran University of Medical
Sciences, Tehran, Iran
H. L. Kaufman
Department of General Surgery and Immunology and
Microbiology, Rush University Medical Center, Rush
University Cancer Center, Chicago, IL, USA

1.1

Introduction

Cancer is a life-threatening disease, which can
involve all human organs and tissues. It is the
second leading cause of death and is responsible
for 25% of all deaths in the USA. It is estimated
that around 1.7 million of new cases of cancer of
any site will be diagnosed in 2018  in the USA,
and an estimated 609,640 people will die of this
disease [1]. The major cancers in adults include
lung, breast, prostate, and colorectal cancer. In
addition, 4613 adolescents and young adults aged
15–19  years old were diagnosed with invasive
cancers. Among all invasive cancers, lymphoma

was the most common cancer (20%), followed by
invasive skin cancer (15%), male genital system
cancer (11%), and endocrine system cancer
(11%) [2]. The overall incidence of all type of
cancers has been falling on average 1.1% each
year over the last 10  years. In addition, death
related to cancer has been decreased on average
1.5% each year over 2006–2015 [3].
Many cancer predisposing factors have been
recognized; it has been found that cancer incidence is significantly associated with age from
10 to 60  years. Additionally, male gender is at
higher risk of developing cancer compared to
females [2]. Race is another important factor for
cancer development; before 40 years of age, non-­
Hispanic whites and, after 40  years of age,
African-Americans/blacks have the highest incidence [4]. Other risk factors include life style
choices, such as tobacco use, obesity, and lack of
exercise, and environmental factors, such as
exposure to excessive sun, radiation during childhood, human papilloma virus (HPV), human
immunodeficiency virus, and Epstein–Barr virus
(EBV) infection [4].

Cancer can be a life-threatening health problem, especially when the tumor has metastasized
to other organs. Its estimated number of deaths
was 163.5 per 100,000 men and women per year
based on 2011–2015 database of the USA. Lung
and bronchus, colorectal, pancreatic, and breast
cancers are responsible for approximately 50%
of cancer-related deaths. Fortunately, the overall
cancer-related mortality has been decreasing in

recent years. Between 2011 and 2015, the death
rate decreased on an average of 1.8% per year for
men and 1.4% for women. Liver and intrahepatic
bile duct cancer showed the greatest increase in
mortality among both men and women [3].
Cancer survival significantly impacts patients’
quality of life. Five-year mortality rates depend
on several factors; survival is worse among males
over 30 years of age, and the survival gets worse
for patients over 45  years in both males and
females. Non-Hispanic whites have the best survival rate and African-Americans have the worst
survival with survival differences as great as 20%
at 5 years after cancer diagnosis [5]. Furthermore,
the type of cancer is another risk factor for patient
survival. Total mortality rates vary from 6% in
thyroid cancer to 97% in pancreatic cancer [6].

1.2

Cancer Immunity

Cancer immunology has been studied for a long
time; however, the molecular and cellular basis of
tumor immunity is not completely understood.
Advances in understanding the basis of immunosurveillance and progress in the treatment of
infectious disease have had a major impact on the
development of tumor immunotherapy. The modern era of tumor immunology began in the 1950s
when the role of T-cell responses in tissue
allograft rejection was initially identified. Since
then, it has been confirmed that tumors occur in

association with impaired function of T-cells,
indicating the importance of the immune system
in the development and progression of cancer [7].
The identification of tumor-associated antigens,
knowledge of effector T-cell responses, and the
role of regulatory and suppressor T-cell populations are now shaping the use of the immune system to treat cancer.


1  Introduction on Cancer Immunology and Immunotherapy

3

In addition to an improved understanding of
the immune system, significant advances in
understanding the molecular basis of neoplasia
have occurred. Precise control of cellular activity
and metabolism is crucial for proper physiologic
function. Notably, cell division is an important
process that requires precise regulation. The main
difference between tumor cells and normal cells
is lack of growth control during the cell division
process. This uncontrolled cell division can originate from various factors, such as chemical
agents, viral infections, and mutations, that lead
to escape of cells from the checkpoints which
properly control cell division. According to the
type of tumor and proliferation rate, cancers can
be benign or malignant [8]. It has been found that
some tumors are caused by oncogenic viruses
that induce malignant transformation. These
oncogenic viruses can be both RNA and DNA

viruses. Also, viral infection may lead to leukopenia and immunodeficiency, increasing the risk
of malignancy. Therefore, prophylactic immunization against oncogenic viruses (such as EBV,
HPV, and HBV) might be a logical strategy for
prevention of malignancy [9]. Indeed, a vaccine
against the human papilloma virus has shown
significant impact on preventing cervical intraepithelial neoplasia and may prevent development
of cervical carcinoma.

gene expression of a mutant-dominant-negative
TGF-β type II receptor (DNR). In addition, specific T-cells genetically manipulated to produce
IL-12 can overcome the inhibitory effects of
IL-10. On the other hand, tumors may express
FasL and stimulate apoptosis of tumor-­infiltrating
effector T-cells. Small interfering RNA (siRNA)
can be used to knock down the Fas receptor in
tumor-specific CTL, leading to a significant
decrease in their susceptibility to Fas-/FasL-­
mediated apoptosis [11].
The interaction between the immune system
and established cancers is complex, because in
addition to increasing carcinogenesis by various
carcinogens among compromised subjects, cancer
cells themselves can lead to severe immunosuppression. It has been reported that patients involved
with primary immunodeficiency syndromes have
higher risk of cancer development. In a report by
Kersey et al., subjects that had an inherited abnormal lymphoid system were susceptible to malignant transformation and impairment of tumor
immunosurveillance [12]. In addition, tumors produce soluble factors which downregulate the interleukin-2 receptor-α (IL-2Rα), leading to
suppression of T-cell function. Furthermore, established tumors may result in severe protein expenditures in hosts, contributing to impairment of
immune system function [13].

1.3

1.4

 ancer and Immune System
C
Impairment

It has been reported that impaired immune
response can induce tumor growth and prevent
effective antitumor suppression, possibly through
a process of “sneaking through” which allows
improved growth of small tumors rather than
large tumors [10]. Tumors may also produce
immunosuppressive factors, such as interleukin­10 (IL-10), transforming growth factor-β (TGF-­
β), and alpha-fetoprotein, which suppress innate
immune responses against cancer. This has led to
investigations using neutralizing antibodies
against these immunosuppressive factors [7]. In
contrast, tumor-specific cytotoxic T lymphocytes
(CTLs) can be genetically altered to become
resistant to the TGF-β inhibitory effect by trans-

I mmune System Reaction
to Cancer

A critical question is whether cancer cells are
sufficiently different from their normal cellular
counterparts and can thus be recognized by the
immune system. The immune system also produces a group of complementary markers with

protective effects against cancer and other
immunologic or inflammatory stresses. These
markers include proteins released by T-cells and
are generally classified as “cytokines.”
Cytokines include interleukins, interferons,
tumor-necrosis factors (TNF), and lymphocytederived growth factors. The production of
tumor-specific a­ntibodies and/or activation of
tumor antigen-­
specific T-cells target tumorassociated antigens typically found on the cell


N. Rezaei et al.

4

membrane. Studies have suggested that vaccination in the presence of complements can lead to
tumor lysis. While incompletely defined, several
soluble and cellular mediators of tumor rejection have been described, including complement
factors, active macrophages, T-cells, and NK
cells. While T-cells require antigen specificity,
the soluble and cellular mechanisms of the
innate immune response can recognize the
malignant phenotype in the absence of antigen
specificity [14].
Since most tumor-associated antigens are self-­
proteins, the immune response is largely weak and
patients may develop immune tolerance to tumorassociated antigens. Furthermore, the cells of the
immune system may not adequately penetrate to
the internal tumor microenvironment, resulting in
slower immune-mediated tumor elimination.

However, it is possible that the immune system
may be more effective in controlling tumor growth
rate rather than tumor regression [10]. Recently, it
has been found that nutrition also plays a crucial
role in protection against human cancer, and normal levels of zinc are required for protection
against the detrimental effects of various immunosuppressive cytokines [15].

1.5

Genetic and Environmental
Carcinogenesis

It has been found that genetic factors are as
important as environmental carcinogens. Trials
have tested carcinogenesis of retrovirus infection
between different breeds of animals. A unique
carcinogen resulted in disparate outcomes among
different breeds, indicating the importance of
genetic background in the progression of cancer.
Environmental factors may also suppress immune
responses and dysregulate immunosurveillance
mechanisms [16].

1.5.1 C
 ancer Cells Escape from Host
Immunosurveillance
Antigens that distinguish tumor cells from normal cells depend on the histologic origin of the
tumor. Tumor-associated antigens may be viral in

origin, represent mutated self-antigens, be

cancer-­testis antigens which are expressed only
by tumor cells and normal testes, or be normal
differentiation antigens. Thus, tumor cells may
express similar antigens to normal cells, allowing
tumor cells to escape immune system attack
through induction of innate and/or peripheral tolerance. A corollary to this is that immunotherapy
or stimulation of immune responses to some
tumor-associated antigens may lead to damage of
normal tissues and organs, as exemplified by the
development of autoimmunity induced by anti-­
CTLA-­
4 or anti-PD-1 monoclonal antibody
(mAb) treatment [17].
A number of complex mechanisms have been
suggested for the escape of cancer cells from host
immunosurveillance. Tumors alter their characteristics by decreased expression of immunogenic
tumor-associated antigens, MHC class I molecules, beta2-microglobulin, and costimulatory
molecules, which mediate the activation of
T-cells. Another strategy resulting in failure of
tumor immunosurveillance could be the expression of very low levels of antigens, unable to stimulate an immune response. Under some
circumstances, such as failure of the immune
response to induce a rapid response, cancer cells
may proliferate rapidly. Further strategies for
escape of tumor cells from immunosurveillance
are based on inhibitory tumor-mediated signaling
by CTLs, as occurs through changes in cell death
receptor signaling. Other strategies which allow
tumor cells to evade the immune system are the
secretion immunosuppressive molecules dampening tumor-reactive effector T-cells and the induction of regulatory and/or suppressor cells [18].
To date, most direct evidence on tumor immunosurveillance originates from experimental

studies in animal models. These models have
supported the potential for antitumor immunity
via vaccination, as, for example, by ­administration
of inactivated cancer cells or through removal of
a primary tumor. In addition, antitumor immunity
can be adoptively transferred through administration of tumor-reactive T lymphocytes. The complexities of immunotherapy are evident as nearly
all immune system components can influence
tumor growth and progression. Although there is
evidence for antitumor immunity in humans, and


1  Introduction on Cancer Immunology and Immunotherapy

several new agents have gained regulatory
approval for cancer therapy, further investigation
is warranted to increase the impact of tumor
immunotherapy for more cancer patients [19].

1.5.2 Cancer Immunodiagnosis
Nowadays, new immunomolecular diagnostic
approaches have been suggested for tumor detection. Monoclonal antibodies marked with radioisotopes have been used for in vivo diagnosis of
small tumor foci. In addition, monoclonal antibodies have been used for in vitro recognition of
the cell of origin for tumors with poor differentiation. Immunodiagnostics have also been used to
determine the extent of metastatic disease, especially metastasis to the bone marrow [20].

1.6

Cancer Treatment

Systemic cancer treatment is based on four general therapeutic approaches: (1) chemotherapy,

which contains a wide group of cytotoxic drugs
that interfere with cell division and DNA synthesis; (2) hormonal therapy, which contains drugs
that interfere with growth signaling via tumor
cell hormone receptors; (3) targeted therapy,
which involves a novel group of antibodies and
small-molecule kinase suppressors that principally target proteins crucial in cancer cell growth
signaling pathways; and (4) immunotherapy,
which targets the induction or expansion of antitumor immune responses [21].

1.6.1 Cancer Immunotherapy
Tumor immunotherapy is a novel therapeutic
approach for cancer treatment, with increasing
clinical benefits. Tumor immunotherapy is based
on strategies which improve the cancer-related
immune response through either promoting components of the immune system that mediate an
effective immune response or via suppressing
components that inhibit the immune response.
Two current approaches commonly used for
immunotherapy are allogeneic bone marrow

5

transplantation and mAbs targeting cancer cells or
T-cell checkpoints [22]. Recently, various other
approaches have been tested such as injection of
cytokines. FDA recently approved injection of
PEG-IFN-a2b in high-risk melanoma [23].
Initially, anticancer vaccines were considered
for prevention and treatment of various tumors
[22]. It is estimated that more than 15% of human

cancers are caused by viral infection [24].
Vaccine-based immunotherapy may, thus, be
most useful for virus-induced cancers. Consistent
with this hypothesis, a 50% complete remission
(CR) of HPV-associated vulvar intraepithelial
neoplasia grade III (VINIII) has been reported
[25]. An attenuated, oncolytic herpes simplex
type 1, which is genetically engineered to secrete
granulocyte-macrophage colony-stimulating factor (GM-CSF), has been developed for cancer
therapy. This oncolytic immunotherapeutic agent
has been injected to the tumor mass and has had
beneficial effects in the treatment of melanoma
and head and neck squamous cell carcinoma
[26]. Although vaccine-based therapy has not
been effective in some types of cancer, there are
studies that have shown an overall survival benefit compared to placebo therapy [27]. FDA
recently approved a vaccination therapy using
dendritic cells for prostate cancer [28].
Another immune-targeted approach is mAbs
which blocks T-cell checkpoints functioning to
suppress T-cell responses. Cytotoxic T
lymphocyte-­associated antigen 4 (CTLA-4) is a
member of a large family of molecules regulating
T-cell immune responses. CTLA-4 is expressed
on CD4+ and CD8+ T-cells, as well as on
FOXP3+ regulatory T-cells [29]. Administration
of mAbs targeting human CTLA-4 leads to the
rejection of established tumors in a small cohort
of patients with metastatic melanoma and demonstrated improved overall survival in patients
with metastatic melanoma, resulting in US FDA

approval for the treatment of metastatic melanoma [30]. Recent trial showed survival benefit
of ipilimumab, a CTLA-4 inhibitor, in setting of
metastatic melanoma and also after resection of
stage III melanoma [31, 32].
Monoclonal antibodies which block other
T-cell checkpoints, such as the programmed cell
death protein 1 (PDCD1/PD-1), programmed cell


N. Rezaei et al.

6

death ligand 1 (PD-L1/CD274), CD276 (B7H3)
antigen, V-set domain-containing T-cell function
inhibitor 1 (B7x), and B and T lymphocyte attenuator, have also entered clinical trials. In addition, recent trials have demonstrated significant
therapeutic activity in several types of cancer,
including melanoma, metastatic urothelial carcinoma, gastric cancer, hepatocellular cancer,
colorectal cancer, renal cell carcinoma, non-­
small cell lung carcinoma, and ovarian cancer
[33–38]. It has been reported that PD-L1 expression by tumor cells is associated with poor clinical outcome and may be associated with clinical
response to anti-PD-1 and anti-PD-L1 therapy.
Also, ligation of PD-L1 leads to inactivation of
tumor-infiltrating cells [39]. On the other hand,
regulatory T-cells have an immunosuppressive
role in the tumor microenvironment. Studies of
anti-PD-1 and anti-PD-L1 are in progress.
Moreover, the combination of these agents with
anti-CTLA-4 and other immunotherapy strategies has yielded promising results.
The combination of antitumor vaccines with

agents targeting the IL-12 receptor resulted in
conflicting results. This may be due to the upregulation of IL-12 receptor by both activated T effector cells and regulatory T-cells [40]. Thus, new
approaches focused on more specific targeting of
regulatory T-cells which reduce their suppressive
effects on the immune system are necessary.
Adoptive T-cell therapy (ACT) has been described
as an effective therapeutic approach for cancer
immunotherapy in early phase clinical trials. In
this method, a large number of tumor-specific
T-cells derived from peripheral blood, or preferably from the tumor microenvironment (with or
without genetic manipulation to express a highaffinity antigen-­specific T-cell receptor, or TCR),
are adoptively transferred to patients with established tumors [41]. ACT mostly relies on endogenous T-cell repertoire; recent advancements
allow induction chimeric antigen receptors
(CARs). In CAR T-cell (CAR-T) therapy, T-cells
of patients with B-cell tumors are transfected with
anti-CD19 and in result, T-cells will gain the
capacity to recognize B-cells in all stages of
development. The first CAR-T was recently
approved by FDA based on phase 2 trial which
showed a dramatic complete response in 83% of

patients within 3  months of infusion [42, 43].
Chemotherapy-­
mediated cell death leads to
immune responses in a drug-induced biochemical
cell death cascade-­dependent manner, suggesting
beneficial effects of chemotherapy and immunotherapy, in combination [44]. It seems that future
goals of tumor immunotherapy are headed
towards chemoimmunotherapy. Potential candidates for this combination approach include antitumor vaccines, Toll-like receptor (TLR) signaling
pathway agonists/antagonists, cytokines, and

mAbs targeting T-cell checkpoints, such as
CTLA-4, PD-1, or PD-L1/2 [45]. Also, it seems
that radiation and radiofrequency ablation are
future candidates for combination therapy with
immunotherapy [46]. Although immunotherapy
and its combination with other therapeutic
approaches such as radioimmunotherapy may be
beneficial for tumor treatment, there are several
limitations that need to be addressed; defining the
optimal target patient, optimal biological dose,
and schedule, the need for better trial designs
incorporating appropriate clinical endpoints, and
the identification and validation of predictive biomarkers are just a few points to note [22].

1.6.2 Cancer Cell “Switch”
Cancer cells can switch on genes mostly related
to the earlier embryonic stages of development.
During rapid proliferation of cancer cells, precise
orchestrated enzyme formation needed for suitable metabolism of its different components
might get unbalanced, and products which are
not observed in normal dividing cells are produced [47]. Recently, it has been reported that
these biochemical “switches” lead to uncontrolled multiplication of cancer cells. One switch
has been found for a type of leukemia. It has been
suggested that targeting tumor switches can make
treatment of cancers very simple [19].
Nonetheless, it is unclear how this may be used to
optimize tumor immunotherapy.
Since cancer immunology is a highly complex
process, further research is needed to more completely understand how the immune system recognizes and eradicates cancer. In this book, we
will describe a variety of novel mechanisms cur-

1  Introduction on Cancer Immunology and Immunotherapy

rently under investigation for mediating aspects
of tumor immunology with a particular focus on
promising therapeutic approaches, producing a
complete comprehensive up-to-date textbook.

1.7

Concluding Remarks

Cancer is a life-threatening health problem which
is related to several genetic and environmental
risk factors that manipulate immune system function. Cancers themselves produce immunosuppressor factors to impair cells division check
points, leading to uncontrolled proliferation of
cancer cells. Importantly, tumor cells have
learned how to escape from immune system
attack via presenting of similar antigens to normal cells and expression of very low levels of
antigens. Therefore, diagnosis of tumors and
their progression is not easy. Recently, immunodiagnostic methods are shown to be helpful in the
diagnosis of cancers and determining the extent
of metastasis. On the other hand, classic treatment of cancers led to unsatisfactory results, and
intelligent immunological approaches, such as
regulatory T-cell targeting, adoptive T-cell
administration, and combination of immunotherapy and chemotherapy are addressed. Results of
antitumor vaccines, Toll-like receptor (TLR) signaling pathway agonists/antagonists, cytokines,
and mAbs targeting T-cell checkpoints, such as
CTLA-4, PD-1, or PDL-1/2 are promising.

However, due to the high complexity of the cancer immunology, still a lot of gaps exist in this
field that indicate the necessity of further research
for complete understanding of cancers’ immunological behaviors and emerging of more novel
immunotherapeutic strategies.

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2

Role of Innate Immunity in Cancers
and Antitumor Response
Masahisa Jinushi and Muhammad Baghdadi

Contents
2.1

Introduction

 11

2.2
2.2.1
2.2.2

2.2.3
2.2.4
2.2.5
2.2.6

Role of Innate Immune Cells in Cancer and Antitumor Immunity
 atural Killer (NK) Cells
N
Natural Killer T (NKT) Cells
γδ-T Cells
Macrophages
Dendritic Cells
Granulocytes

 12
 12
 13
 13
 14
 14
 14

2.3

 he Role of Innate Immune Receptors on Innate Immune Cells in Cancer
T
and Antitumor Immunity
 15
Toll-like Receptors (TLRs)
 15

RIG-I-Like Helicases (RLHs)
 15
NOD-like Receptors (NLRs)
 15
Phagocytosis Receptors
 16
C-Type Lectin-like Receptors (CLRs)
 16
NK Cell Receptors
 18
B7 Family
 19

2.3.1
2.3.2
2.3.3
2.3.4
2.3.5
2.3.6
2.3.7

 he Role of Effectors Produced from Innate Immune Cells in Cancer
T
and Antitumor Immunity
2.4.1 Interferons (IFNs)
2.4.2 Other Cytokines
2.4.3 Chemokines
2.4

2.5

Concluding Remarks

 22

References

M. Jinushi (*)
Research Center for Infection-Associated Cancer,
Institute for Genetic Medicine, Hokkaido University,
Sapporo, Japan
e-mail:
M. Baghdadi
Division of Immunobiology, Institute for Genetic
Medicine, Hokkaido University, Sapporo, Japan

 19
 19
 20
 21

 23

2.1

Introduction

Cellular components of the innate immune system serve as a “first line of defense” against
tumorigenic cells. Recognition of transformed
cells by pattern-recognition receptor (PRRs) on

the innate immune cells activates specialized

© Springer Nature Switzerland AG 2020
N. Rezaei (ed.), Cancer Immunology, />
11


M. Jinushi and M. Baghdadi

12

inflammatory signaling cascades, including transcription factor nuclear factor-kappa B (NF-κB)
and interferon regulatory transcription factor
(IRF), which lead to the release of various cytokines and chemokines attracting and activating
effector lymphocytes at the tumor site. In addition, effector cells kill transformed cells through
the activation of perforin or death receptor-­
mediated pathways, as well as secretion of cytokines necessary for the initiation of immune
responses against transformed cells [1, 2].
However, some tumor cells escape from the
innate immune machinery, which leads to the
dysfunction of innate immune compartment, signaling pathways, and effector functions. This
manipulation of innate immune systems by tumor
microenvironments includes impairment of antigen processing and presentation by antigen-­
presenting cells (APCs) [3], inhibition of innate
immune signaling pathways [4, 5], and anti-­
inflammatory cytokines such as IL-10 and transforming growth factor-β (TGF-β) [6, 7].
Moreover, tumors manipulate innate immune
systems to create protumorigenic environments,
which lead to further tumor progression and
metastasis. Therefore, it is critical to clarify the

molecular mechanisms through which the interaction between tumors and innate immune systems is modified during different phases of
tumorigenesis.
In this chapter, we describe the general functions of innate immunity in cancer and antitumor
host response. In addition, an overview is provided on the mechanism through which coordinated actions of innate immune signals and their
downstream effectors have an impact on the
immunosurveillance and immune subversion
within the tumor microenvironment.

2.2

 ole of Innate Immune Cells
R
in Cancer and Antitumor
Immunity

2.2.1 Natural Killer (NK) Cells
NK cells are important effector cells for protection against viruses and some tumors, since

NK-cell-depleted mice were more susceptible to
3-methylcholanthrene (MCA)-induced tumors
[8]. Chemokines, such as CXCL12 and
CXCL3L1, are key factors for NK migration to
tumor sites [9], where they play an important role
in the tumor immunosurveillance [10]. NK cells
recognize and eliminate transformed cells by
releasing perforin or death signal-associated
receptors such as FAS and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) [11–
13]. NK cells secrete interferon gamma (IFN-γ)
which helps to activate T-cell-mediated immunity and suppress tumor angiogenesis [14, 15].
Moreover, various innate immune networks such

as cytokines and PRR recognition systems play
an important role in stimulating effector functions of NK cells as discussed later.
NK cells have the ability to distinguish transformed cells from normal cells by recognizing a
variety of cell surface receptors, including killer
activation receptors (KARs), killer inhibitory
receptors (KIRs), natural killer group two member D (NKG2D), DNAX-accessory molecule
(DNAM), etc., which will be discussed later in
this chapter. For example, KIRs on NK cells have
a high affinity to the specific alleles in HLA class
I molecules, transducing an inhibitory signal to
the NK cells and preventing it from eliminating
nontransformed cells. However, deletion of a
single allele in HLA class I and/or induction of
activating receptors, such as NKG2D ligands,
which frequently occurs on transformed cells,
triggers effector functions of NK cells against
tumor cells [10, 16]. Recent studies have focused
on “licensing” NK cells to become functionally
competent through the interaction with self-MHC
molecules. Ly49C is an inhibitory receptor
expressed on a subset of NK cells, which interact
with self-MHC molecules on target cells, and
plays an unexpected role in enabling immature
NK cells to develop into functioning, mature
cells. On the other hand, Ly49C-negative NK
cells are considered as “non-licensed” and remain
at an immature stage [17]. These evolutionary
processes of NK cell development and activation
may help explain why donor NK cells administrated to leukemia patients during bone marrow
transplantation do not always show antitumor

2  Role of Innate Immunity in Cancers and Antitumor Response

13

effects [18]. The NK cell-mediated cytotoxic
activities mediate the release of granule contents
(perforin and granzyme) onto the surface of the
tumor cell [19].
The interaction between NK cells and dendritic cells (DCs) is crucial for the amplification
of innate responses and the induction of potent
adaptive immunity. Immature DCs are susceptible to NK-cell-mediated cytolysis [20], while
mature DCs are activated by NK cells through
cytokines (TNF-α and IFN-γ) and receptor
(NKp30 and NKG2D)-mediated mechanisms
[21, 22]. On the other hand, activated DCs trigger
effector activities of NK cells, such as IFN-γ production, proliferation, and cytotoxic activities
[23]. In addition, treatment with TLR3 agonist
polyinosinic-polycytidylic acid (Poly (I: C)) triggers DCs to activate antitumor activities of NK
cells [24, 25]. Thus, the reciprocal interaction
between NK and DC regulates the direction and
quality of antitumor immunity, which is important for the development of effective cancer
immunotherapy.

which also activates NK and CD8+ T-cells. NKT
cell activities are also important for granulocyte
macrophage colony-stimulating factor (GM-CSF)
and IL-12-based cytokine strategies [29, 30].
Recent reports have identified subpopulations of

NKT cells which secrete TH1 or TH2 cytokines
and thus play different roles in the pathogenesis
of many diseases. For example, CD4− NKT cells
serve as potent effectors for triggering tumor
rejection in various murine tumor models, while
CD4+ NKT cells contribute to the pathogenesis of
allergic diseases and tumors by promoting the
release of IL-4, IL-5, and IL-13 [31, 32]. Indeed,
IL-13 released from NKT cells antagonizes
tumor immunosurveillance by promoting TGF-β
secretion from Gr-1+ myeloid suppressor cells
[33, 34]. Thus, the identification of factors influencing the differentiation of specific NKT cell
subsets during tumor development is important in
order to optimize the therapeutic interventions
which utilize NKT cell functions against tumors.

2.2.2 Natural Killer T (NKT) Cells

Although γδ-T cells represent a small population
among T lymphocytes, they share several features with innate immune cells. γδ-T cells show
high frequencies in intraepithelial lymphocytes
(IELs) in the skin and gut mucosa and possess a
distinct T-cell receptor on their surface with limited diversity, which may serve as a
­pattern-­recognition receptor [35]. Moreover,
γδ-T cells lack CD4 and CD8 expressed by αβ-T
cells and express a number of molecules shared
with NK cells or APCs, such as Fc gamma RIII/
CD16 and PRRs. γδ-T cells also recognize lipidderived antigens and function as professional
phagocytes which recognize and ingest apoptotic
tumor cells and may influence antitumor immune

responses [36, 37].
Mice lacking γδ-T cells showed increased
incidence of chemically induced sarcoma and
spindle cell carcinoma, indicating the importance
of these cells in tumor immunosurveillance [38].
In addition, γδ-T cells express NKG2D receptors
and interact with their ligands on transformed
cells, leading to enhanced cytotoxic activities and

NKT cells are innate lymphocytes which share
features of both NK cells and T-cells. NKT cells
express particular NK cell markers such as
CD161 or NKR-P1, in addition to an invariant
T-cell receptor alpha chain (Vα14-Jα18 in mice
and Vα24-Jα18  in humans) [26]. The invariant
T-cell receptor alpha chain is specific for glycolipid antigens presented by CD1d, which is an
MHC class I-related molecule expressed on
antigen-­presenting cells and also found in some
tumor cells. NKT cells were shown to play a role
in the tumor immunosurveillance, since Jα18−/−
mice showed increased susceptibility to chemically induced tumors and experimentally induced
metastases [27]. Moreover, the administration of
α-galactosylceramide, a natural lipid isolated
from marine sponges which efficiently binds to
CD1d and thus activates NKT cells, induces antitumor immune responses against established
murine tumors [28]. The antitumor activities of
NKT cells are mediated by IFN-γ production,

2.2.3 γδ-T Cells