The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

Cancer Cell. 2021 Feb 8;39(2):154-173. doi: 10.1016/j.ccell.2020.10.001. Epub 2020 Oct 29.

Abstract

Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed.

Keywords: biomarker; cancer therapy; genetics; immunotherapy; mutattional load.

Publication types

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

MeSH terms

  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology*
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immunotherapy / methods
  • Major Histocompatibility Complex / genetics
  • Major Histocompatibility Complex / immunology
  • Mutation / genetics*
  • Mutation / immunology*
  • Neoplasms / genetics*
  • Neoplasms / immunology*
  • Neoplasms / therapy
  • T-Lymphocytes / immunology

Substances

  • Biomarkers, Tumor
  • Immune Checkpoint Inhibitors