Resistance of Cancer Cells to CTL Mediated Immunotherapy

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Preface

In 1909, Paul Ehrlich proposed that the immune system can recognize and destroy
nascent tumor cells. A century later, this principle has been applied successfully for
the treatment of patients with various cancers by the use of monoclonal antibodies,
adoptively transferred T-cells, genetic amplification of T-cells bearing high affinity
TCR, ADCs, CAR T-cells and check point blocking antibodies (see below).
Immunotherapy against cancer has recently experienced significant translational
clinical applications in the treatment of many cancer types. We witnessed a few
decades ago the initial clinical application of T-cell-mediated immunotherapy, ini-
tially by the ex vivo culture and activation of cancer patients BPMCs with IL-2, to
generate LAK cells and, subsequently, the culture and propagation of TILs from
cancer tissues and their adoptive transfer into the patients. Subsequently, various
modalities have been examined and applied in cancer, such as ex vivo DCs pulsed
with tumor lysates or tumor peptides and administered into the patients with growth
factors. In addition, several cancer vaccines have been developed. Further, targeting
T-reg cells and MDCS resulted in enhancing the anti-tumor T-cell response. A num-
ber of successfully current immunotherapies in cancer patients, including check
point targeted antibodies (e.g., anti-CTLA-4, PD-1, and PDL-1) and adoptive T-cell
therapies (e.g., genetically transduced T-cell receptors and CARs), are reported to
be clinically effective in the treatment of advanced cancers, many of which are
resistant to conventional chemotherapy and radiation. The likelihood of responsive-
ness to these immunotherapies differs strongly depending on tumor type. Targeting
check points resulted in significant responses in melanoma, renal cell carcinoma,
and non-small cell lung cancer. For CARs, significant clinical responses have been
achieved in lymphomas. All of the aforementioned is a testimony to the important
role of immunotherapy mediated by T-cells and antibodies that have resulted in the
new generation of targeted therapies and reduced toxicity encountered by conven-
tional chemotherapy and radiotherapy. Several of the aforementioned immunother-
apy strategies were effective in the treatment of drug-resistant tumor cells. However,
there is still a subset of nonresponsive patients who have a cancer with either a natu-
rally acquired resistance or an induced intrinsic resistance to such therapies.

v
vi Preface

The successful requirements for an adoptive and optimal T-cell response consist
of three key elements: the ability to induce a T-cell response; the ability to infiltrate
into the tumor microenvironment; and the ability to kill the tumor cells. Most anti-
cancer cellular and humoral therapies have given little attention to the generally
encountered tumor cell resistance to cytotoxic activities mediated by such therapies.
In fact, tumor cells develop several mechanisms to escape tumor cell death. Tumor
cell resistance may be responsible, in large part, for the fact that many cancer
patients fail to respond to cytotoxic immunotherapy in the presence of anti-tumor
cytotoxic T-effector cells and antibodies.
Clearly, one of the important, and not completely exploited, area in cancer immu-
notherapy is the underlying mechanisms of tumor cell resistance to CTL and anti-
body-mediated cytotoxicities. Several reported studies explored the underlying
molecular bases of tumor cell resistance to CTL and shed new light on the improve-
ment of current immunotherapy of cancer and that could significantly improve the
clinical response. Resistance of Cancer Cells to CTL-Mediated Immunotherapy
reviews, in large part, several of the mechanisms underlying the tumor cell resis-
tance to CTL-Mediated cytotoxicity, and suggests several means to overcome the
resistance by the use of combination treatments with agents targeting resistance in
combination with CTL-Mediated immunotherapy. This volume comprises the con-
tributions of leaders in the field, and provides numerous examples of molecular
bases of CTL resistance. (While this volume does not cover the field in its entirety,
due to the vast scope of the subject, subsequent volumes under consideration will
cover other areas of CTL resistance in cancer and their clinical implications.)
This volume is divided into four parts. Part I, Factors Regulating Resistance to
CTL Cytotoxicity, consists of five review chapters. Doctors Maccalli and colleagues
reviewed “Resistance of Cancer Stem Cells to Cell-Mediated Immune Responses.”
It is clear that, in the majority of cancers, cancer stem cells (CSCs) are believed to
be responsible, in large part, for tumor initiation, progression, metastasis, and resis-
tance to cytotoxic therapies. CSCs have been reported to escape immune surveil-
lance, though they exhibit antigenic molecules that can be targeted for
immunotherapy, rescuing both the new growth and resistance to CTL-Mediated
therapy. Doctors Dolstra and colleagues reviewed “Role of Co-inhibitory Molecules
in Tumor Escape from CTL Attack.” Tumor cells may express co-inhibitory mole-
cules (CIMs) that can severely inhibit CD-8 T-cell cytotoxicity. These inhibitory
molecules on the cancer cell surface, such as PDL-1, will inhibit CTL cytotoxic
activity via interaction and cell signaling of PD-1 on the surface of CTL. In addi-
tion, CIMs such as CTLA-4, LAG-3, BTLA, Tim-3, and CD200R have been impli-
cated in the inhibition of CTL functions. The authors have discussed the role each
of the above CIMs and, as well, suggest various approaches to inhibit their activities
and restore cytotoxic activity. Doctors Seliger and Bergner reviewed “Role of the
Non-classical HLA Class I Antigens for Immune Escape.” One of the mechanisms
of tumor escape from immune surveillance is the overexpression of the non-classi-
cal class I HLA-G+ antigen that is often overexpressed in solid and hematopoietic
tumors. This overexpression leads to its interaction with inhibitory receptors ILT2,
Preface vii

ILT4, and KIR2DL4. HLA-G+ tumors are associated with poor clinical outcomes.
The inhibition of HLA-G can increase the sensitivity to tumor cells to CTL and NK
cytotoxicities. The authors describe the role of HLA-G+ as a therapeutic target.
Doctors Mami-Chouaib and colleagues reviewed “Integrins: Friends or Foes of
Antitumor Cytotoxic T Lymphocyte Response.” The authors describe the role of
integrins and their ligands in the regulation of T-cell effector functions that result in
CTL activation and triggering of their cytotoxic machinery. Of particular interest is
the authors’ description of the integrins CD103 and LFA-1 and their respective
ligands, E-cadherin and ICAM-1, in the regulation of T-cell effector functions. Also
discussed is the importance of integrin-antagonists in cancer immunotherapy.
Doctors Noonan and Murphy reviewed “Cytotoxic T Lymphocytes and their
Granzymes: An Overview.” In addition to several immunotherapeutic strategies,
including antibodies and adoptive transfer of CTLs, novel strategies are aimed at the
cell death pathways including granzymes and death ligands (Fas-L TNFalpha
TRAIL). In this review, examples of granzymes-mediated cell death using the pro-
totype of granzyme-bound immunotoxin therapy are discussed. In addition, in this
review, the authors discuss the initiation and the activation of the effector functions
of CTL and how they can be used in cancer immunotherapy.
Part II, “Influence of the Tumor Microenvironment on the Resistance to CTL
Cytotoxicity,” consists of three review chapters. Doctors Chouaib and colleagues
reviewed “Hypoxia: A Formidable Saboteur of the Anti-tumor Response.” The
tumor microenvironment (TME), in addition to modulating the anti-tumor response,
fosters resistance of tumor cells to CTL cytotoxicity. This review emphasizes the
influence of hypoxic stress that impacts angiogenesis, tumor progression, and
immune tolerance. It includes a discussion on how hypoxia in TME protects tumor
cells by modulation of various molecular signaling pathways in the tumor cells and
rendering them viable, proliferative, and resistant to CTL. The authors suggest that
hypoxia is a target for tumor reactivity to CTL. Doctors Mutis and colleagues
reviewed “Mechanisms and Modulation of Tumor Microenvironment-Induced
Immune Resistance.” The authors discuss the mechanism by which the TME regu-
lates the resistance of tumor cells to CTL cytotoxicity. The authors discuss the mod-
ulation of intrinsic, extrinsic, and granzyme/perforin-mediated pathways of
apoptosis by the TME and have used multiple myeloma as a cancer model. As well,
they discuss strategies to override the resistance of tumor cells to CTL-Mediated
immunotherapies. Doctors Sandra Hodge and Greg Hodge reviewed “Evasion of
Cytotoxic Lymphocyte and Pulmonary Macrophage Mediated Immune Responses
in Lung Cancer.” The authors discuss the regulation of tumor cell resistance to CTL
cytotoxic therapy, and describe the resistance of lung cancer cells to granzyme
B-mediated attack through the expression of a specific inhibitor (such as the intra-
cellular serine protease inhibitor PI-9). PI-9 is expressed in CTLs and protects the
tumor cells to killing by granzyme B. The authors cite studies that report that PI-9
expression positively correlated with cancer stage among patients with solid and
hematologic malignancies, suggesting that targeting PI-9 may be a strategy to
improve immunotherapy in lung cancers.
viii Preface

Part III, “Resistance to Death Ligands-Mediated Apoptosis and Sensitization”

consists of four review chapters. Doctor Bonavida reviewed “Sensitization of
Immune-Resistant Tumor Cells to CTL-Mediated Apoptosis via Interference at the
Dysregulated NF-/Snail/YY1/PI3K/RKIP/PTEN Resistant Loop.” He discusses the
mechanisms by which tumor cells develop resistance to CTL-Mediated apoptosis
via a dysregulated loop consisting of the NF-kB/Snail/YY1/RKIP/PTEN. This dys-
regulated loop further regulates cell growth, proliferation, MET, metastasis, and the
resistance to both CTL and chemotherapeutic drugs. The role of each of the gene
products in the loop and its direct involvement in the regulation of the above func-
tions and, in particular, to CTL-Mediated apoptosis via death ligands (Fas-L, TNFa,
DR4, and DR5) is discussed. Also discussed is the manner in which each of the gene
products in the loop has potential for reversal of resistance as well as inhibition of
tumor cell growth and metastasis. Several examples are provided with different
agents that target different gene products of the loop and resulted in the reversal of
resistance to CTL cytotoxicity. Doctors Zhang and colleagues reviewed “Overcoming
Cancer Cell Resistance to Death Receptor Targeted Therapies.” Targeting death
receptors for cancer treatment has been explored in both the laboratory and in
human clinical trials. Among the death ligands that are not toxic to normal tissues,
TRAIL, is being investigated in clinical trials through the use of either recombinant
TRAIL or agonist antibodies to TRAIL receptors DR4 and DR5. While these stud-
ies are ongoing clinically, both alone and in combination with conventional chemo-
therapy, it must be noted that many patient cancer cells are resistant to such therapies
and require sensitizing agents that can be used in combination to reverse resistance.
The authors discuss various approaches to reverse resistance. Doctors Chen and col-
leagues reviewed “Pancreatic Cancer Resistance to TRAIL Therapy: Regulators of
the Death Inducing Signaling Complex.” The authors discuss the resistance of pan-
creatic cancer to TRAIL-induced apoptosis. They have identified several factors in
the death receptor activated DISC (which include FLIP, calmodulin, Src, and PARP-
1) that contribute to the resistance of cancer cells to death receptor-mediated apop-
tosis. Also discussed are mechanisms that regulate the DISC that result in the
resistance of TRAIL apoptosis. In addition, they suggest, for pancreatic cancer,
various therapeutic targets for immunotherapy. Doctors Thiery and colleagues
reviewed “Resistance of Carcinoma Cells to CTL-Mediated Immunotherapy.” The
authors discuss the role of EMT and cancer stemness in the resistance to both chemo
and CTL-Mediated therapeutics. As well, they explored the immunological synapse
and how it is affected by EMT and discuss the manner in which the inhibition of
EMT can restore cytotoxic immune function.
Part IV, “Future Directions” consists of two chapter reviews. Doctors Kawakami
and colleagues reviewed “Cancer Induced Immunosuppression and Its Modulation
by Signal Inhibitors.” The authors describe various signal-mediated pathways that
regulate the immune response, and how signal inhibitors may enhance anti-tumor
responses. The authors suggest personalized treatments (as the oncogenic signal
activities are different for each cancer patient). They also consider and recommend
personalized treatment for immunotherapy. Doctors Mehrotra and colleagues
Preface ix

reviewed “Quality of CTL Therapies: A Changing Landscape.” The authors discuss

the various mechanisms by which tumor cells escape immune surveillance and
discuss several strategies that they recommend be investigated in order to restore
the immune functions and, in particular, the response of tumor cells to T-cellmediated
therapy. This chapter also provides various challenges for consideration in the
future.

Benjamin Bonavida
Salem Chouaib
Acknowledgements

The editors wish to acknowledge the significant and continuous help and assistance
provided throughout the development of this book by Joy Evangeline Bramble,
Emily Janakiram, and Michael Koy of Springer. In addition, the editors wish to
acknowledge the excellent technical assistance of Kathy Nguyen in both the editing
and finalization of the contents of this volume.

xi
Contents

Part I Factors Regulating Resistance to CTL Cytotoxicity

1 Resistance of Cancer Stem Cells to Cell-Mediated
Immune Responses................................................................................. 3
Veronica Catalano, Cecilia Eleuteri, Gaia Campoccia,
Gianluca Giacobini, Mariangela Zane, Giorgio Stassi,
Giorgio Parmiani, and Cristina Maccalli
2 Role of Co-inhibitory Molecules in Tumor Escape
from CTL Attack .................................................................................... 31
Wieger J. Norde, Willemijn Hobo, and Harry Dolstra
3 Role of the Non-classical HLA Class I Antigens
for Immune Escape ................................................................................ 59
Barbara Seliger and Simon Jasinski-Bergner
4 Integrins: Friends or Foes of Antitumor Cytotoxic
T Lymphocyte Response ........................................................................ 73
Marie Boutet, Stephanie Cognac, and Fathia Mami-Chouaib
5 Cytotoxic T Lymphocytes and Their Granzymes:
An Overview ........................................................................................... 91
Janis Noonan and Brona M. Murphy

Part II Influence of the Tumor Microenvironment

on the Resistance to CTL Cytotoxicity
6 Hypoxia: A Formidable Saboteur of the Anti-tumor Response ......... 115
Meriem Hasmim, Yosra Messai, Stéphane Terry,
Bassam Janji, Muhammad Zaeem Noman, and Salem Chouaib

xiii
xiv Contents

7 Mechanisms and Modulation of Tumor

Microenvironment-Induced Immune Resistance ................................ 143
Tuna Mutis, Niels W.C.J. van de Donk, and Richard W.J. Groen
8 Evasion of Cytotoxic Lymphocyte and Pulmonary
Macrophage-Mediated Immune Responses in Lung Cancer............. 159
Sandra Hodge and Greg Hodge

Part III Resistance to Death Ligands-Mediated Apoptosis

and Sensitization
9 Sensitization of Immune-Resistant Tumor Cells
to CTL-Mediated Apoptosis via Interference
at the Dysregulated NF-κB/Snail/YY1/PI3K/RKIP/PTEN
Resistant Loop ........................................................................................ 177
Benjamin Bonavida
10 Overcoming Cancer Cell Resistance to Death Receptor
Targeted Therapies ................................................................................ 209
Julianne D. Twomey, William Hallett, and Baolin Zhang
11 Pancreatic Cancer Resistance to TRAIL Therapy:
Regulators of the Death Inducing Signaling Complex ....................... 235
Yabing Chen, Kaiyu Yuan, and Jay McDonald
12 Epithelial Mesenchymal Transition Influence
on CTL Activity ...................................................................................... 267
Wilfried Engl, Virgile Viasnoff, and Jean Paul Thiery

Part IV Future Directions and Challenges

13 Cancer Induced Immunosuppression
and Its Modulation by Signal Inhibitors.............................................. 287
Yutaka Kawakami, Li Qian, Naoshi Kawamura,
Junichiro Miyazaki, Kinya Tsubota, Tomonari Kinoshita,
Kenta Nakamura, Gaku Ohmura, Ryosuke Satomi, Juri Sugiyama,
Hiroshi Nishio, Taeko Hayakawa, Boryana Popivanova,
Sunthamala Nuchsupha, Tracy Hsin-ju Liu, Hajime Kamijuku,
Chie Kudo-Saito, Nobuo Tsukamoto, Toshiharu Sakurai,
Tomonobu Fujita, and Tomonori Yaguchi
14 Quality of CTL Therapies: A Changing Landscape ........................... 303
Krishnamurthy Thyagarajan, Shilpak Chatterjee,
Pravin Kesarwani, Michael I. Nishimura, and Shikhar Mehrotra

Index ................................................................................................................ 351

 Part I
Factors Regulating Resistance
to CTL Cytotoxicity
Chapter 1
Resistance of Cancer Stem Cells
to Cell-Mediated Immune Responses

Veronica Catalano*, Cecilia Eleuteri*, Gaia Campoccia, Gianluca Giacobini,

Mariangela Zane, Giorgio Stassi, Giorgio Parmiani, and Cristina Maccalli

Abstract In the past decades, the hierarchical organization of tumors, governed by

Cancer Stem Cells (CSCs), have been reported with regard to several tumor types.
Advances in sequencing technologies have demonstrated that diverse genetic CSCs
subclones, derived from the branching evolution, compete with each other within
the tumor mass, thereby contributing to the functional heterogeneity. It is becoming
increasingly clear that epigenetic modifications and microenvironmental influences
are important determinants of tumor fitness resulting in disease progression, recur-
rence and reduced patient survival. Therefore, more effective therapies will require
gaining insights into the role of genetic and non-genetic influences in coordinating
tumor maintenance.
CSCs are believed to be responsible for tumor initiation, progression and resis-
tance to therapeutic agents. Therefore, CSC-targeted therapeutic interventions are
desirable to achieve complete tumor eradication. Immunotherapy can represent a
valuable treatment thanks to its antigen-specificity. The molecular and immunologi-
cal characterizations, though still not definitive, of CSCs revealed their low
efficiency in eliciting adaptive immune responses and the presence of features cor-
relating with escape from immunosurveillance. Nevertheless, CSC-specific mole-
cules may represent novel targets for immunotherapy and immunomodulatory
agents may able to rescue their immunogenicity. This information might be exploited
to design novel CSC-targeting therapies, possibly in association with inhibitors of

*No conflict statement: “No potential conflicts of interest were disclosed.”

V. Catalano • C. Eleuteri • M. Zane • G. Stassi
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy
G. Campoccia • G. Giacobini
Medical Oncology and Immunotherapy, University Hospital of Siena,
V.le Bracci, 16, Siena 53100, Italy
G. Parmiani • C. Maccalli (*)
Medical Oncology and Immunotherapy, University Hospital of Siena,
V.le Bracci, 16, Siena 53100, Italy
NIBIT-Italian Network for Bio-therapy of Tumors, Siena, Italy
e-mail: [email protected]

© Springer International Publishing Switzerland 2015 3

B. Bonavida, S. Chouaib (eds.), Resistance of Cancer Cells to CTL-Mediated
Immunotherapy, Resistance to Targeted Anti-Cancer Therapeutics 7,
DOI 10.1007/978-3-319-17807-3_1
4 V. Catalano et al.

survival pathways and/or with differentiation agents and cytotoxic drugs. These
therapeutic strategies are desirable in order to target the entire cancer and can repre-
sent a promising strategy to achieve complete tumor regression.

Keywords Cancer stem cells • Cancer stem cell markers • Signaling pathways of
cancer stem cells • T cell responses • NK Cells • Immunomodulatory molecules •
CSC-targeted therapies • Immune escape

Abbreviations

ABC ATP-binding cassette

ADAM A disintegrin and metalloprotease
APC Adenomatosis polyposis coli
APCs Antigen presenting cells
APM Antigen processing machinery
B7-H1, 3, 4 B7 homolog family members
BMP Bone morphogenetic protein
CEA Carcino embryonic antigen
CK1 Casein kinase 1
COA-1 Colon antigen-1
CRC Colorectal cancer
CSC Cancer stem cells
CSL CBF1/Su(H)/Lag-1
CXCR-4 C-X-C chemokine receptor type 4
EMT Epithelial-to-mesenchymal transition
Ep-CAM Epithelial cell adhesion molecule
EphB Ephrin B
ESC Embryonic stem cells
FZ Frizzled
GBM Glioblastoma multiforme
GDF-15 Growth differentiation factor 15
Gp100 Glycoprotein 100
GS γ-Secretase
GSK3 Glycogen synthase kinase 3
Hh Hedgehog
HLA Human leukocyte antigen
IDO Indoleamine 2,3-dioxigenase
IFN Interferon
IL-10 Interleukin-10
IL-13α2 α2 chain of IL-13 receptor
IL-4 Interleukin-4
LRP Low-density-lipoprotein-related protein5/6
M Mastermind-like protein 1
1 Immune Evasion by Cancer Stem Cells 5

MAA Melanoma associated antigen

MAGE Melanoma-associated antigen gene
MART-1 Melanoma antigen recognized by T cells
MDSC Myeloid derived suppressor cell
Melan-A Protein melan-A, see also MART-1
MHC Major histocompatibility complex
MSC Mesenchymal stem cell
MUC-1 Mucin 1
NKG2D Natural killer group 2, member D
Notch-IC Receptor intracellular domain
NY-ESO-1 New York esophagus 1 antigen
PD-1 Programmed cell death protein 1
PD-L1 Programmed death ligand 1
PGE2 Prostaglandin E2
PSA Prostate specific antigen
PTCH Patched
R Recombining binding protein suppressor of hairless
Runx2 Runt-related transcription factor 2
SMO Smoothened
STAT3 Signal transducer and activator of transcription 3
SVV-1 Survivin 1
TAA Tumor associated antigen
TCF T-cell factor-1
TGF-β1 Tumor growth factor beta 1
Treg T regulatory cell

1.1 Introduction

According to the classical model of tumorigenesis, every cell of the body is equally
susceptible to acquire an unlimited and uncontrolled proliferative potential, follow-
ing genetic and epigenetic mutations. Clonal evolution of different subclones, dic-
tated by environmental influences and continuing mutagenesis, explains the
phenotypic differences observed in a tumor population [1]. Accumulating evidences
suggest that tumor growth and progression are driven by a subset of cells with
“stemness” properties, called cancer stem cells (CSCs). Located at the top of tumor
hierarchy, these cells possess the long-life capacity to self-renew and generate the
heterogeneous population of differentiated descendants, which constitute the tumor
bulk [2]. The practical translation of this definition is their ability to generate a seri-
ally transplantable phenocopy of the original malignancy when injected into
immuno-compromised mice [3].
From a clinical point of view, CSCs have been defined by multiple resistant
mechanisms against anti-cancer therapies contributing to tumor recurrence and
metastatic dissemination [4]. Similar to normal stem cells, CSCs were reported to