Obstacles for T-lymphocytes in the tumour microenvironment: Therapeutic challenges, advances and opportunities beyond immune checkpoint

EBioMedicine. 2022 Sep:83:104216. doi: 10.1016/j.ebiom.2022.104216. Epub 2022 Aug 17.

Abstract

The tumour microenvironment (TME) imposes a major obstacle to infiltrating T-lymphocytes and suppresses their function. Several immune checkpoint proteins that interfere with ligand/receptor interactions and impede T-cell anti-tumour responses have been identified. Immunotherapies that block immune checkpoints have revolutionized the treatment paradigm for many patients with advanced-stage tumours. However, metabolic constraints and soluble factors that exist within the TME exacerbate the functional exhaustion of tumour-infiltrating T-cells. Here we review these multifactorial constraints and mechanisms - elevated immunosuppressive metabolites and enzymes, nutrient insufficiency, hypoxia, increased acidity, immense amounts of extracellular ATP and adenosine, dysregulated bioenergetic and purinergic signalling, and ionic imbalance - that operate in the TME and collectively suppress T-cell function. We discuss how scientific advances could help overcome the complex TME obstacles for tumour-infiltrating T-lymphocytes, aiming to stimulate further research for developing new therapeutic strategies by harnessing the full potential of the immune system in combating cancer.

Keywords: Immunotherapy; Ionic checkpoint; Tumor-infiltrating lymphocytes; Tumor-interstitial fluid.

Publication types

  • Review

MeSH terms

  • Adenosine
  • Adenosine Triphosphate
  • Humans
  • Immune Checkpoint Proteins
  • Immunotherapy
  • Ligands
  • Neoplasms* / pathology
  • T-Lymphocytes*
  • Tumor Microenvironment

Substances

  • Immune Checkpoint Proteins
  • Ligands
  • Adenosine Triphosphate
  • Adenosine