Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1 - CD8 + Tumor-Infiltrating T Cells

Immunity. 2019 Jan 15;50(1):181-194.e6. doi: 10.1016/j.immuni.2018.11.014. Epub 2019 Jan 8.

Abstract

An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1- TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7/Tcf1 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.

Keywords: CD8(+) T cell; PD-1; Tim-3; cancer; checkpoint blockade; dysfunction; exhaustion; immunotherapy; memory; single-cell.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Hepatitis A Virus Cellular Receptor 2 / antagonists & inhibitors
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Humans
  • Immunologic Memory / genetics
  • Immunotherapy
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / therapy*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • T-Lymphocyte Subsets / immunology*
  • Transcriptome

Substances

  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • HAVCR2 protein, human
  • HNF1A protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Hepatocyte Nuclear Factor 1-alpha
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor