Tumor context dictates reliance on Tcf1 for response to immunotherapy

Stem-like CD8 + T cells are regulated by the transcription factor TCF1 and are key players in the response to immune checkpoint blockade (ICB). However, recent findings indicate that reliance on TCF1 + CD8 + stem-like T cells for ICB efficacy may not be equal across patients or tumor contexts. Here, we uncovered that TCF1-deficient CD8 + T cells showed defective priming in the tumor-draining lymph node of mice bearing poorly immunogenic tumors and that TCF1 regulates optimal T cell responsiveness to low TCR triggering. Importantly, we found that TCF1 was dispensable for therapy response in settings where ICB expanded intra-tumoral transitory effector-like cells. Conversely, TCF1 was required for ICB response in tumors that failed to expand cytotoxic effectors and accumulated Tox + dysfunctional T cells. In the absence of TCF1, dysfunctional T cells became destabilized and shared features with CD8 + T cells found in patients that fail ICB. Our study highlights a role for TCF1 in the early stages of the anti-tumor CD8 + T cell response with important implications for guiding optimal therapeutic interventions in cancers with low frequency of TCF1 + CD8 + T cells and low neoantigen levels. Overall design: We combined cell sorting with high-throughput single-cell RNA (scRNA) sequencing to characterize endogenous tumor-infiltrating wild-type (WT) or TCF1-knock out (KO) CD8+ T cells in the tumor microenvironment of mice challenged with either the colorectal MC38-OVA or the B16-OVA melanoma tumors and treated with isotype or immune checkpoint blockade (ICB) antibodies (anti TIM3 + anti-PDL1). Endogenous CD8+ T cells were sorted from tumors treated with two doses of isotype or ICB at 12 days post tumor injection. In a separate set of experiments we combined cell sorting with high-throughput single-cell RNA (scRNA) sequencing to characterize adoptively transferred tumor-specific WT or TCF1-KO OTI T cells present in the tumor-draining lymph node (TDLN) of B16-OVA or MC38-OVA-bearing mice, three days post T cell transfer and after one dose of isotype or ICB treatment.