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Cancer Immunology, Immunotherapy

, Volume 68, Issue 10, pp 1689–1700 | Cite as

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

  • Michael Friedrich
  • Simon Jasinski-Bergner
  • Maria-Filothei Lazaridou
  • Karthikeyan Subbarayan
  • Chiara Massa
  • Sandy Tretbar
  • Anja Mueller
  • Diana Handke
  • Katharina Biehl
  • Jürgen Bukur
  • Marco Donia
  • Ofer Mandelboim
  • Barbara SeligerEmail author
Focussed Research Review

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.

Keywords

Tumor Immune escape MHC Immunotherapy Resistance TIMO XIV 

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

Notes

Acknowledgements

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

Author contributions

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.

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Michael Friedrich
    • 1
  • Simon Jasinski-Bergner
    • 1
  • Maria-Filothei Lazaridou
    • 1
  • Karthikeyan Subbarayan
    • 1
  • Chiara Massa
    • 1
  • Sandy Tretbar
    • 1
  • Anja Mueller
    • 1
  • Diana Handke
    • 1
  • Katharina Biehl
    • 1
  • Jürgen Bukur
    • 1
  • Marco Donia
    • 2
  • Ofer Mandelboim
    • 3
  • Barbara Seliger
    • 1
    Email author
  1. 1.Institute of Medical ImmunologyMartin Luther University Halle-WittenbergHalle (Saale)Germany
  2. 2.Department of Oncology, Herlev HospitalUniversity of CopenhagenHerlevDenmark
  3. 3.Department of Immunology, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael

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