CD226hiCD8+ T Cells Are a Prerequisite for Anti-TIGIT Immunotherapy

Cancer Immunol Res. 2020 Jul;8(7):912-925. doi: 10.1158/2326-6066.CIR-19-0877. Epub 2020 Apr 7.


Clinical trials are evaluating the efficacy of anti-TIGIT for use as single-agent therapy or in combination with programmed death 1 (PD-1)/programmed death-ligand 1 blockade. How and whether a TIGIT blockade will synergize with immunotherapies is not clear. Here, we show that CD226loCD8+ T cells accumulate at the tumor site and have an exhausted phenotype with impaired functionality. In contrast, CD226hiCD8+ tumor-infiltrating T cells possess greater self-renewal capacity and responsiveness. Anti-TIGIT treatment selectively affects CD226hiCD8+ T cells by promoting CD226 phosphorylation at tyrosine 322. CD226 agonist antibody-mediated activation of CD226 augments the effect of TIGIT blockade on CD8+ T-cell responses. Finally, mFOLFIRINOX treatment, which increases CD226hiCD8+ T cells in patients with pancreatic ductal adenocarcinoma, potentiates the effects of TIGIT or PD-1 blockade. Our results implicate CD226 as a predictive biomarker for cancer immunotherapy and suggest that increasing numbers of CD226hiCD8+ T cells may improve responses to anti-TIGIT therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Antineoplastic Agents, Immunological / pharmacology*
  • Biomarkers, Tumor / immunology
  • Biomarkers, Tumor / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Immunotherapy / methods*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / therapy*
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Immunologic / immunology*


  • Antigens, Differentiation, T-Lymphocyte
  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor
  • CD226 antigen
  • Receptors, Immunologic
  • TIGIT protein, human