PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy

J Immunother Cancer. 2020 Nov;8(2):e001631. doi: 10.1136/jitc-2020-001631.


Background: Clinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated.

Methods: We isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally after therapy. Using multiparameter flow cytometry and cell sorting, we isolated four subsets of CD8+ T cells, based on PD-1 and TIGIT expression profiles. We performed phenotypic characterization, T cell receptor sequencing, targeted transcriptomic analysis and antitumor reactivity assays to thoroughly characterize each of these subsets.

Results: We documented that the frequency of circulating PD-1+TIGIT+ (DPOS) CD8+ T-cells after 1 month of anti-PD-1 therapy was associated with clinical response and overall survival. This DPOS T-cell population was enriched in highly activated T-cells, tumor-specific and emerging T-cell clonotypes and T lymphocytes overexpressing CXCR5, a key marker of the CD8 cytotoxic follicular T cell population. Additionally, transcriptomic profiling defined a specific gene signature for this population as well as the overexpression of specific pathways associated with the therapeutic response.

Conclusions: Our results provide a convincing rationale for monitoring this PD-1+TIGIT+ circulating population as an early cellular-based marker of therapeutic response to anti-PD-1 therapy.

Keywords: CD8-Positive T-Lymphocytes; costimulatory and inhibitory T-Cell receptors; immunotherapy; melanoma; programmed cell death 1 receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinoma, Merkel Cell / blood
  • Carcinoma, Merkel Cell / drug therapy
  • Carcinoma, Merkel Cell / immunology*
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Melanoma / blood
  • Melanoma / drug therapy
  • Melanoma / immunology*
  • Predictive Value of Tests
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / biosynthesis*
  • Programmed Cell Death 1 Receptor / blood
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, CXCR5 / immunology
  • Receptors, Immunologic / biosynthesis*
  • Receptors, Immunologic / blood
  • Receptors, Immunologic / immunology
  • T-Lymphocyte Subsets / immunology


  • CXCR5 protein, human
  • Immune Checkpoint Inhibitors
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, CXCR5
  • Receptors, Immunologic
  • TIGIT protein, human