A network of intra and extra-tumoural cytotoxic T cells with precursor and residency features constrained by TGF-b

Anti-tumour immunity is limited by loss of T cell function and sustained expression of inhibitory receptors or immune checkpoints, including PD-1, a state known as T cell exhaustion. Exhausted T cells are maintained by precursors of exhausted T (TPEX) cells, that self-renew and generate effector cells, particularly in response to therapeutic immune checkpoint blockade (ICB). Similarly, tissue-resident memory T (TRM)-like cells have been implicated in tumour control and ICB response. However, the factors governing TPEX and TRM-like cell differentiation and function within the tumour environment, their relationship, and their response to ICB, remain insufficiently understood. Using single cell RNA sequencing and innovative mouse models that enable the identification and targeting of both TPEX and TRM-like cells within and outside the tumour microenvironment, we systemically dissect the developmental and functional relationship between tumour-responsive TPEX cells in the tumour microenvironment and in lymph nodes. We show that within the tumour microenvironment, TPEX cells and their progeny could acquire a tissue residency program that limits their contribution to tumour control and response to checkpoint inhibition. In contrast, stem-like TPEX cells, dependent on the transcription factor MYB and located within the tumour-draining lymph nodes (tdLN), were essential for fueling CD8+ T cell tumour infiltration and response to ICB. We identify TGF-β as the common factor enforcing residency of TPEX cells in the tumour and limiting the abundance of stem-like TPEX cells in tdLN. Finally, we provide evidence for the presence of a similar network of intra- and extratumoural CD8+ T cells in human cancer, exhibiting precursor and residency characteristics that is constrained by TGF-β.