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

## TL;DR

This paper explores why some tumors resist immune checkpoint therapies by preventing T-cell activation and infiltration, and suggests new treatment strategies.

## Contribution

The paper identifies mechanisms of T-cell desertification and exclusion in tumors and proposes novel therapeutic approaches to overcome resistance to immune checkpoint therapies.

## Key findings

- Tumors can become 'cold' by either preventing T-cell generation (desert tumors) or blocking T-cell infiltration (excluded tumors).
- Desert tumors target antigen-presenting cells with suppressive factors, while excluded tumors use fibrosis and immunosuppression to block T-cell access.
- Understanding these mechanisms could lead to new immunotherapies that restore T-cell priming and tumor infiltration.

## Abstract

Immune 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.