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

By I. Siddiqui, Karin Schaeuble, Vijaykumar Chennupati, S. F. Marraco, Sandra P. Calderon-Copete, D. Ferreira, Santiago J. Carmona, L. Scarpellino, David Gfeller, S. Pradervand and 3 more. Immunity, 2019

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Summary 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. Graphical Abstract Figure. No Caption available. HighlightsMouse and human tumors harbor relatively undifferentiated Tcf1+PD‐1+CD8+ T cellsThese intratumoral cells have expansion, regeneration, and differentiation capacityThey produce differentiated Tcf1−PD‐1+CD8+ T cells in response to immunotherapyThese stem‐like cells are critical for tumor control in response to immunotherapy &NA; Since chronic activation promotes terminal T cell differentiation (exhaustion), it has remained unclear how checkpoint blockade mediates a proliferative response of tumor‐infiltrating T cells. Siddiqui et al. identify intratumoral, tumor‐reactive Tcf1+PD‐1+CD8+ T cells that display stem‐like properties and that promote tumor control in response to vaccination and checkpoint blockade immunotherapy.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/5ff7b8f34dd22db68bdd1118040bef57b3e42bd6

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Citations in the corpus

Neoadjuvant checkpoint blockade for cancer immunotherapy (2020, background): “showed that Tcf1 antigen– experienced T cells within the TME are the primary pool of tumor-specific T cells activated by CPI (34).”
Pan-cancer single-cell landscape of tumor-infiltrating T cells (2021, background): “TCF7 has been considered to be the key regulator of stem-like T cells in tumors (24).”
Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms (2020, background): “Indeed, Tex cells are a major cell type responding to PD-1 blockade (Huang et al., 2017; Miller et al., 2019; Siddiqui et al., 2019; Thommen et al., 2018), and trials are underway to reinvigorate Tex cells in human chronic viral infections (Wykes and Lewin, 2018).”