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

Abstract

Graphical AbstractHighlights d Mouse and human tumors harbor relatively undifferentiated Tcf1 + PD-1 + CD8 + T cells d These intratumoral cells have expansion, regeneration, and differentiation capacity d They produce differentiated Tcf1 À PD-1 + CD8 + T cells in response to immunotherapy d These stem-like cells are critical for tumor control in response to immunotherapy In BriefSince chronic activation promotes terminal T cell differentiation (exhaustion), it has remained unclear how checkpoint blockade mediates a proliferative response of tumorinfiltrating 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. SUMMARYCheckpoint 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 À 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.

Chimeric antigen receptor T cell persistence and memory cell formation

“…These precursors have arrested cell cycle and do not proliferate upon Ag or cytokine exposure . The fully transcriptional network responsible for transition from precursor to mature memory cells is poorly known, but it appears that transcription factors such as TCF‐1 and FoxO1 play a crucial role . Re‐entry into the cell cycle activation may be critical for effector cell to memory cell transformation—similar to the model somatic cell reprogramming to induced pluripotent stem cells through enforced expression of oct‐4, sox2, klf4 and c‐myc .…”

“…Because the epigenetic status of memory T cells reflects that of undifferentiated T cells, one of the major challenges is the generation of CAR T memory in the face of the potent ex vivo stimuli necessary for optimal CAR T cell transduction and expansion (see Figure ). In comparison to physiological expansion of antigen reactive lymphocytes, CAR T cells undergo in vitro CD3/CD28 stimulation, transduction, further CD3/CD28 stimulation, followed by expansion in recombinant cytokines in the weeks prior to adoptive transfer (Figure ) . Given that all T cells present in the ex vivo culture preparation will have been triggered via CD3 and CD28, by definition the product lacks strictly “naive” T cells.…”

“…However, it does not appear to reverse exhaustion in majority of T cells . It was recently demonstrated that a proportion of supposedly “exhausted” tumor‐infiltrating T cells that express TCF1 (see below) preferentially respond to anti‐PD1 treatment and could transform into self‐renewing memory cells …”

“…H3K27me3 and H3K9me3) on the newly synthesised DNA strand, enabling the binding of memory T cell–associated transcription factors (e.g. TCF 7 and LEF 1) that reprogramme the T cell into more memory cell‐like state . [The color version of this figure can be viewed at www.wileyonlinelibrary.com/journal/icb]…”

“…Although the terms of T cell memory and persistence may sometimes be used interchangeably, a working definition of memory T cell function must include longevity and self‐renewal . In terms of persistence, functionally active anti‐cancer T cells, without typical memory features, may persist in favorable conditions in the host, particularly when the manifestation of exhaustion‐related and AICD is minimized . Strategies to prolong the lifespan and activity of non‐memory T cells may still contribute markedly to the anti‐tumor response.…”