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Resistance to Immunotherapy: Mechanisms and Means for Overcoming

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Immunotherapy

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1342))

Abstract

Immune checkpoint blockade transformed cancer therapy during the last decade. However, durable responses remain uncommon, early and late relapses occur over the course of treatment, and many patients with PD-L1-expressing tumors do not respond to PD-(L)1 blockade. In addition, while some malignancies exhibit inherent resistance to treatment, others develop adaptations that allow them to evade antitumor immunity after a period of response. It is crucial to understand the pathophysiology of the tumor-immune system interplay and the mechanisms of immune escape in order to circumvent primary and acquired resistance. Here we provide an outline of the most well-defined mechanisms of resistance and shed light on ongoing efforts to reinvigorate immunoreactivity.

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Abbreviations

B2M:

beta-2 microglobulin

CAF:

cancer-associated fibroblast

CAR:

chimeric antigen receptor

CCR:

chemokine receptor

CR:

complete response

CRC:

colorectal carcinoma

CSF:

colony-stimulating factor

CSF1R:

colony-stimulating factor 1 receptor

CTL:

cytotoxic T lymphocyte

CTLA-4:

cytotoxic T-lymphocyte-associated protein 4

CXCL:

CXC chemokine ligand

CXCR:

CXC chemokine receptor

DC:

dendritic cell

EGFR:

epidermal growth factor receptor

FasL:

Fas ligand

FcγR:

Fcγ receptor

FDA:

US Food and Drug Administration

HIF-1:

hypoxia-inducible factor 1

ICAM:

intercellular adhesion molecule

ICB:

immune checkpoint blockade

ICI:

immune checkpoint inhibitor

IDO:

indoleamine 2,3-dioxygenase

IFN-γ:

interferon-gamma

iRECIST:

immune response evaluation criteria in solid tumors

iRs:

immune downregulating checkpoints

ITIM:

immunoreceptor tyrosine-based inhibitory motif

JAK:

Janus kinase

LAG-3:

lymphocyte-activation gene 3

LAIR-1:

leukocyte-associated immunoglobulin-like receptor 1

mAb:

monoclonal antibody

MAPK:

mitogen-activated protein kinase

MDSC:

myeloid-derived suppressor cell

MHC:

major histocompatibility complex

MICA-B:

MHC-I-related chain B

M-MDSC:

monocytic subtype of myeloid-derived suppressor cell

MMR:

mismatch repair

MPR:

major pathologic response

MSI-H:

microsatellite instability high

NK:

natural killer

NSCLC:

nonsmall cell lung cancer

OS:

overall survival

PBMC:

peripheral blood mononuclear cell

PD:

progressive disease

PD-1:

programmed cell death protein 1

PD-L1:

programmed death-ligand 1

PFS:

progression-free survival

PI3K:

phosphatidylinositol 3-kinase

PR:

partial response

PTEN:

phosphatase and tensin homolog

RCC:

renal cell carcinoma

RECIST:

response evaluation criteria in solid tumors

SD:

stable disease

STAT:

signal transducers and activators of transcription

STING:

stimulator of interferon genes

TAM:

tumor-associated macrophage

Teff:

effector T cell

TGF-β:

transforming growth factor beta

Th:

T-helper cell

TIGIT:

T-cell immunoreceptor with Ig and ITIM domains

TIL:

tumor-infiltrating lymphocyte

TIM-3:

T-cell immunoglobulin 3

TKI:

tyrosine kinase inhibitor

TLR:

toll-like receptor

TMB:

tumor mutational burden

TME:

tumor microenvironment

TNBC:

triple-negative breast cancer

TNF-α:

tumor necrosis factor alpha

Treg:

regulatory T cell

VCAM:

vascular cell adhesion molecule

VEGF:

vascular endothelial growth factor

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  1. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

    Mohamad A. Salkeni

  2. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    John Y. Shin & James L. Gulley

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  2. John Y. Shin
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  3. James L. Gulley
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Correspondence to Mohamad A. Salkeni or James L. Gulley .

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Editors and Affiliations

  1. Professor, Dept. of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Aung Naing

  2. Assistant Professor, Service Chief of Adult Allergy & Immunology, Division of Immunology, Allergy & Retrovirology Baylor College of Medicine and Texas Children’ Hospital, Houston, TX, USA

    Joud Hajjar

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Salkeni, M.A., Shin, J.Y., Gulley, J.L. (2021). Resistance to Immunotherapy: Mechanisms and Means for Overcoming. In: Naing, A., Hajjar, J. (eds) Immunotherapy. Advances in Experimental Medicine and Biology, vol 1342. Springer, Cham. https://doi.org/10.1007/978-3-030-79308-1_2

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