Rewriting History: Epigenetic Reprogramming of CD8+ T Cell Differentiation to Enhance Immunotherapy

Trends Immunol. 2020 Aug;41(8):665-675. doi: 10.1016/ Epub 2020 Jul 2.


The full potential of T cell-based immunotherapies remains limited by a variety of T cell extrinsic and intrinsic immunosuppressive mechanisms that can become imprinted to stably reduce the antitumor ability of T cells. Here, we discuss recent insights into memory CD8+ T cell differentiation and exhaustion and the association of these differentiation states with clinical outcomes during immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapeutic modalities. We consider the barriers limiting immunotherapy with a focus on epigenetic regulation impeding efficacy of adoptively transferred T cells and other approaches that augment T cell responses such as immune checkpoint blockade. Furthermore, we outline conceptual and technical breakthroughs that can be applied to existing therapeutic approaches and to the development of novel cutting-edge strategies.

Keywords: CAR T cells; T cell exhaustion; cancer immunotherapy; epigenetics; immune checkpoint blockade.

Publication types

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

MeSH terms

  • CD8-Positive T-Lymphocytes* / cytology
  • CD8-Positive T-Lymphocytes* / immunology
  • Cell Differentiation*
  • Epigenesis, Genetic*
  • Immunotherapy* / trends
  • Lymphocyte Activation / genetics