TLR Stimulation during T-cell Activation Lowers PD-1 Expression on CD8+ T Cells

Cancer Immunol Res. 2018 Nov;6(11):1364-1374. doi: 10.1158/2326-6066.CIR-18-0243. Epub 2018 Sep 10.

Abstract

Expression of T-cell checkpoint receptors can compromise antitumor immunity. Blockade of these receptors, notably PD-1 and LAG-3, which become expressed during T-cell activation with vaccination, can improve antitumor immunity. We evaluated whether T-cell checkpoint expression could be separated from T-cell activation in the context of innate immune stimulation with TLR agonists. We found that ligands for TLR1/2, TLR7, and TLR9 led to a decrease in expression of PD-1 on antigen-activated CD8+ T cells. These effects were mediated by IL12 released by professional antigen-presenting cells. In two separate tumor models, treatment with antitumor vaccines combined with TLR1/2 or TLR7 ligands induced antigen-specific CD8+ T cells with lower PD-1 expression and improved antitumor immunity. These findings highlight the role of innate immune activation during effector T-cell development and suggest that at least one mechanism by which specific TLR agonists can be strategically used as vaccine adjuvants is by modulating the expression of PD-1 during CD8+ T-cell activation. Cancer Immunol Res; 6(11); 1364-74. ©2018 AACR.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Aminoquinolines / pharmacology
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Female
  • Gene Expression Regulation / drug effects
  • Imidazoles / pharmacology
  • Interleukin-12 Subunit p35 / metabolism
  • Lymphocyte Activation / immunology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms, Experimental / immunology
  • Ovalbumin / pharmacology
  • Peptide Fragments / pharmacology
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism*
  • Toll-Like Receptors / agonists*
  • Toll-Like Receptors / immunology

Substances

  • Aminoquinolines
  • Il12a protein, mouse
  • Imidazoles
  • Interleukin-12 Subunit p35
  • OVA-8
  • Pdcd1 protein, mouse
  • Peptide Fragments
  • Programmed Cell Death 1 Receptor
  • Toll-Like Receptors
  • gardiquimod
  • Ovalbumin