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. 2019 Jan 15;50(1):195-211.e10.
doi: 10.1016/j.immuni.2018.12.021. Epub 2019 Jan 8.

Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy

Imran Siddiqui  1 , Karin Schaeuble  1 , Vijaykumar Chennupati  1 , Silvia A Fuertes Marraco  1 , Sandra Calderon-Copete  2 , Daniela Pais Ferreira  1 , Santiago J Carmona  3 , Leonardo Scarpellino  4 , David Gfeller  3 , Sylvain Pradervand  2 , Sanjiv A Luther  4 , Daniel E Speiser  1 , Werner Held  5
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Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy

Imran Siddiqui et al. Immunity. .
Free article

Abstract

Checkpoint blockade mediates a proliferative response of tumor-infiltrating CD8+ T lymphocytes (TILs). The origin of this response has remained elusive because chronic activation promotes terminal differentiation or exhaustion of tumor-specific T cells. Here we identified a subset of tumor-reactive TILs bearing hallmarks of exhausted cells and central memory cells, including expression of the checkpoint protein PD-1 and the transcription factor Tcf1. Tcf1+PD-1+ TILs mediated the proliferative response to immunotherapy, generating both Tcf1+PD-1+ and differentiated Tcf1-PD-1+ cells. Ablation of Tcf1+PD-1+ TILs restricted responses to immunotherapy. Tcf1 was not required for the generation of Tcf1+PD-1+ TILs but was essential for the stem-like functions of these cells. Human TCF1+PD-1+ cells were detected among tumor-reactive CD8+ T cells in the blood of melanoma patients and among TILs of primary melanomas. Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.

Keywords: T cell exhaustion; T cell factor 1; T cell reinvigoration; cancer immunotherapy; checkpoint blockade; memory-like T cells; stem-like T cells; therapeutic vaccination.

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