Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

Cancer Cell. 2017 Mar 13;31(3):311-325. doi: 10.1016/j.ccell.2017.02.008.

Abstract

T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles.

Keywords: T cell dysfunction; TME; adoptive T cell therapy; genetic engineering; immunotherapy; tumor microenvironment.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acids / metabolism
  • Cytotoxicity, Immunologic
  • Fatty Acids / metabolism
  • Genes, p53
  • Glucose / metabolism
  • Humans
  • Lactic Acid / metabolism
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Neoplasms / therapy
  • Receptors, Antigen, T-Cell / physiology
  • T-Lymphocytes / immunology*
  • Tumor Microenvironment*

Substances

  • Amino Acids
  • Fatty Acids
  • Receptors, Antigen, T-Cell
  • Lactic Acid
  • Glucose