Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy

Abstract

Immunotherapy aims to activate the immune system to fight cancer in a very specific and targeted manner. Despite the success of different immunotherapeutic strategies, in particular antibodies directed against checkpoints as well as adoptive T-cell therapy, the response of patients is limited in different types of cancers. This attributes to escape of the tumor from immune surveillance and development of acquired resistances during therapy. In this review, the different evasion and resistance mechanisms that limit the efficacy of immunotherapies targeting tumor-associated antigens presented by major histocompatibility complex molecules on the surface of the malignant cells are summarized. Overcoming these escape mechanisms is a great challenge, but might lead to a better clinical outcome of patients and is therefore currently a major focus of research.

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Abbreviations

DAC:

5-Aza-2′-desoxycytidine

3′ UTR:

3′ Untranslated region

ACT:

Adoptive cell therapy

APM:

Antigen processing and presentation machinery

BGN:

Biglycan

CTL:

Cytotoxic T lymphocyte

CTLA-4:

Cytotoxic T-lymphocyte associated protein-4

DCN:

Decorin

ER:

Endoplasmic reticulum

ERAP:

Endoplasmic reticulum aminopeptidase

EBV:

Epstein–Barr virus

GAS:

Gamma activated site

HC:

Heavy chain

HNRNPR:

Heterogeneous nuclear ribonucleoprotein R

HCMV:

Human cytomegalovirus

iCP:

Immune checkpoint

iCPI:

Immune checkpoint inhibitor

im-miRNAs:

Immune modulatory miRNAs

ILT:

Inhibitory receptor Ig-like transcript

IFN:

Interferon

IRF:

Interferon regulated factor

ISRE:

Interferon-sensitive response element

LOH:

Loss of heterozygosity

Luc:

Luciferase

MHC:

Major histocompatibility complex

β2-m:

β2-Microglobulin

miRNA:

MicroRNA

MSI:

Microsatellite instability

Mex:

Muscle excess

MDSC:

Myeloid-derived suppressor cells

NLRC5:

NOD-like receptor family and acid domain-containing protein 5

OS:

Overall survival

Treg:

Regulatory T cell(s)

RBP:

RNA-binding proteins

RNAseq:

RNA sequencing

STAT:

Signal transducer and activator of transcription

SNP:

Single nucleotide polymorphism

SLRP:

Small leucine-rich proteoglycan

TPN:

Tapasin

TCGA:

The Cancer Genome Atlas

TGF-β:

Transforming growth factor β

TAP:

Transporter associated with antigen processing

TAF:

Tumor-associated fibroblast(s)

TAM:

Tumor-associated macrophages

TAN:

Tumor-associated neutrophil(s)

TMB:

Tumor mutational burden

TME:

Tumor microenvironment

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Acknowledgements

We would like to thank Maria Heise for excellent secretarial help in preparing the manuscript.

Funding

This work was funded by the German Research Foundation (DFG; SE 581/22-1 and RTG, 1591/2-B4), the German Israeli Foundation for Scientific Research and Development (GIF; I-37-414.11-2016), and the Mildred Scheel Foundation.

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Barbara Seliger planned the manuscript. All the authors contributed in writing parts of the manuscript. Michael Friedrich, Simon Jasinski-Bergner, Barbara Seliger discussed the contents, while Michael Friedrich created the figures.

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Correspondence to Barbara Seliger.

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This paper is a Focussed Research Review based on a presentation given at the Fourteenth Workshop & Symposium “Tumor Immunology meets Oncology” (TIMO XIV), held in Halle (Saale), Germany, 24th–26th May 2018. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.

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Friedrich, M., Jasinski-Bergner, S., Lazaridou, MF. et al. Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy. Cancer Immunol Immunother 68, 1689–1700 (2019). https://doi.org/10.1007/s00262-019-02373-1

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Keywords

  • Tumor
  • Immune escape
  • MHC
  • Immunotherapy
  • Resistance
  • TIMO XIV