Resistance to immune checkpoint therapies by tumour-induced T-cell desertification and exclusion: key mechanisms, prognostication and new therapeutic opportunities

Author:

Wang Mona MengORCID,Coupland Sarah E.,Aittokallio TeroORCID,Figueiredo Carlos R.ORCID

Abstract

AbstractImmune checkpoint therapies (ICT) can reinvigorate the effector functions of anti-tumour T cells, improving cancer patient outcomes. Anti-tumour T cells are initially formed during their first contact (priming) with tumour antigens by antigen-presenting cells (APCs). Unfortunately, many patients are refractory to ICT because their tumours are considered to be ‘cold’ tumours—i.e., they do not allow the generation of T cells (so-called ‘desert’ tumours) or the infiltration of existing anti-tumour T cells (T-cell-excluded tumours). Desert tumours disturb antigen processing and priming of T cells by targeting APCs with suppressive tumour factors derived from their genetic instabilities. In contrast, T-cell-excluded tumours are characterised by blocking effective anti-tumour T lymphocytes infiltrating cancer masses by obstacles, such as fibrosis and tumour-cell-induced immunosuppression. This review delves into critical mechanisms by which cancer cells induce T-cell ‘desertification’ and ‘exclusion’ in ICT refractory tumours. Filling the gaps in our knowledge regarding these pro-tumoral mechanisms will aid researchers in developing novel class immunotherapies that aim at restoring T-cell generation with more efficient priming by APCs and leukocyte tumour trafficking. Such developments are expected to unleash the clinical benefit of ICT in refractory patients.

Funder

Emil Aaltosen Säätiö

Sigrid Juséliuksen Säätiö

Academy of Finland

InFlames Flagship

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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