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


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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Fig. 1
Fig. 2




3′ UTR:

3′ Untranslated region


Adoptive cell therapy


Antigen processing and presentation machinery




Cytotoxic T lymphocyte


Cytotoxic T-lymphocyte associated protein-4




Endoplasmic reticulum


Endoplasmic reticulum aminopeptidase


Epstein–Barr virus


Gamma activated site


Heavy chain


Heterogeneous nuclear ribonucleoprotein R


Human cytomegalovirus


Immune checkpoint


Immune checkpoint inhibitor


Immune modulatory miRNAs


Inhibitory receptor Ig-like transcript




Interferon regulated factor


Interferon-sensitive response element


Loss of heterozygosity




Major histocompatibility complex






Microsatellite instability


Muscle excess


Myeloid-derived suppressor cells


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


Overall survival


Regulatory T cell(s)


RNA-binding proteins


RNA sequencing


Signal transducer and activator of transcription


Single nucleotide polymorphism


Small leucine-rich proteoglycan




The Cancer Genome Atlas


Transforming growth factor β


Transporter associated with antigen processing


Tumor-associated fibroblast(s)


Tumor-associated macrophages


Tumor-associated neutrophil(s)


Tumor mutational burden


Tumor microenvironment


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


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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  • Tumor
  • Immune escape
  • MHC
  • Immunotherapy
  • Resistance