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


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.


Tumor Immune escape MHC Immunotherapy Resistance TIMO XIV 




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



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.


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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