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Translational Biomarkers and Rationale Strategies to Overcome Resistance to Immune Checkpoint Inhibitors in Solid Tumors

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Tumor Microenvironment

Part of the book series: Cancer Treatment and Research ((CTAR,volume 180))

Abstract

Immune checkpoint inhibitors (ICIs) targeting the programed cell-death protein 1 (PD-1) or its ligand PD-L1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways have improved the survival for patients with solid tumors. Unfortunately, durable clinical responses are seen in only 10–40% of patients at the cost of potential immune-related adverse events. In the tumor microenvironment (TME), tumor cells can influence the microenvironment by releasing extracellular signals and generating peripheral immune tolerance, while the immune cells can affect the initiation, growth, proliferation, and evolution of cancer cells. Currently, translational biomarkers that predict responses to ICIs include high PD-L1 tumor proportion score, defective DNA mismatch repair, high microsatellite instability, and possibly high tumor mutational burden. Characterization of immune cells in the TME, such as tumor-infiltrating lymphocytes, T-cell gene expression profile, T-cell receptor sequencing, and peripheral blood biomarkers are being explored as promising biomarkers. Recent neoadjuvant studies have integrated the real-time assessment of both molecular and immune biomarkers using the tissue and blood specimens simultaneously and longitudinally. This review summarizes the current knowledge and progress in developing translational biomarkers and rational combinational strategies to improve the efficacy of ICIs tailored to individual cancer patients.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ALC:

Absolute lymphocyte counts

ANC:

Absolute neutrophil counts

APCs:

Antigen-presenting cells

B2M:

Beta-2-microglobulin

BRCA:

Breast cancer

bTMB:

Blood tumor mutation burden

CAMLs:

Cancer-associated macrophage-like cells

CCR:

C-C Motif Chemokine Receptor

CE:

Conformité Européene

CRP:

C-reaction protein

CTL:

Cytotoxic T lymphocytes

CTLA-4:

Cytotoxic T-lymphocyte antigen 4

CTCs:

Circulating tumor cells

CXCR:

C-X-C Motif Chemokine Receptor

dMMR:

Deficient mismatch repair

dNLR:

Derived neutrophil-to-lymphocyte ratio

ECM:

Extracellular matrix 

ELISPOT:

Enzyme-linked immune absorbent spot

FFPE:

Formalin-fixed paraffin-embedded

FOXP3:

Forkhead box P3

GEP:

Gene expression profile

HLA:

Human leukocyte antigen

HNSCC:

Head and neck squamous cell carcinomas

ICIs:

Immune checkpoint inhibitors

ICOS:

Inducible costimulator

IDO:

Indoleamine-pyrrole 2,3-dioxygenase

IFN-γ:

Interferon-gamma

IFNGR1:

IFN-γ receptor 1

IFNGR2:

IFN-γ receptor 2

IRF1:

IFN regulatory factor 1

IHC:

Immunohistochemical stain

irAEs:

Immune-related adverse events

IL:

Interleukin,

JAK:

Janus kinase

LAG3:

Lymphocyte-activation protein 3

LDH:

Lactate dehydrogenase

LIPI:

Lung immune prognostic index

NGS:

Next-generation sequencing

NSCLC:

Non-small cell lung cancer

mAbs:

Monoclonal antibodies

MDSC:

Myeloid-derived suppressor cell

MHC:

Major histocompatibility complex

MSI-H:

Microsatellite instability–high

NK:

Natural killer

OS:

Overall survival

PBMC:

Peripheral blood mononuclear cell

pCR:

Pathological complete response

PD-1:

Programed cell-death protein 1

PD-L1:

Programed cell-death protein ligand 1

PDX:

Patient-derived xenograft

PFS:

Progression-free survival

STAT:

Signal transducer and activator of transcription

STING:

Stimulator of interferon gene

TAAs:

Tumor-associated antigens

TCR:

T cell receptor

TGF-β:

Transforming growth factor-beta

TILs:

Tumor-infiltrating lymphocytes

TIGIT:

T cell immunoreceptor with Ig and ITIM domains

TIM3:

T cell immunoglobulin and mucin domain-3

TMB:

Tumor mutational burden

TME:

Tumor microenvironment

TPS:

Total proportion score

WES:

Whole exome sequencing

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California, Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA

    Justin A. Chen, Weijie Ma & Tianhong Li

  2. Translational Oncology, Early Oncology Clinical Research, Merck Research Laboratories, Rahway, NJ07065, USA

    Jianda Yuan

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  1. Justin A. Chen
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  2. Weijie Ma
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  3. Jianda Yuan
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  4. Tianhong Li
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Correspondence to Tianhong Li .

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  1. Department of Immuno-Oncology, City of Hope National Medical Center, Duarte, CA, USA

    Peter P. Lee

  2. Refuge Biotechnologies, Menlo Park, CA, USA

    Francesco M. Marincola

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Chen, J.A., Ma, W., Yuan, J., Li, T. (2020). Translational Biomarkers and Rationale Strategies to Overcome Resistance to Immune Checkpoint Inhibitors in Solid Tumors. In: Lee, P., Marincola, F. (eds) Tumor Microenvironment. Cancer Treatment and Research, vol 180. Springer, Cham. https://doi.org/10.1007/978-3-030-38862-1_9

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