Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy

Immunity. 2020 Oct 13;53(4):824-839.e10. doi: 10.1016/j.immuni.2020.09.006.


CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226-/- mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.

Keywords: CD226 (DNAM-1); CD8(+) T lymphocytes; Eomesodermin (Eomes); T cell exhaustion; TCR signaling; co-stimulation; immune checkpoint blockade; immunotherapy; lymphocyte function-associated antigen 1 (LFA-1); tumor immune escape.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, T-Lymphocyte / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Humans
  • Immune Checkpoint Inhibitors / immunology
  • Immunotherapy / methods
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / immunology*
  • Neoplasms / therapy
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / immunology
  • T-Box Domain Proteins / immunology*
  • Transcriptome / immunology
  • Tumor Microenvironment / immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology


  • Antigens, Differentiation, T-Lymphocyte
  • CD226 antigen
  • EOMES protein, human
  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell
  • T-Box Domain Proteins
  • Tumor Necrosis Factor Receptor Superfamily, Member 9