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Cancer-specific TCF1 + stem-like CD8 + T cells can drive protective anticancer immunity through expansion and effector cell differentiation 1-4 ; however, this response is dysfunctional in tumours. Current cancer immunotherapies 2,5-9 can promote anticancer responses through TCF1 + stem-like CD8 + T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1 + CD8 + T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE 2 ) restricts the proliferative expansion and effector differentiation of TCF1 + CD8 + T cells within tumours, which promotes cancer immune escape. PGE 2 does not affect the priming of TCF1 + CD8 + T cells in draining lymph nodes. PGE 2 acts through EP 2 and EP 4 (EP 2 /EP 4 ) receptor signalling in CD8 + T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 + tumour-infiltrating CD8 + T lymphocytes (TILs). Ablation of EP 2 /EP 4 signalling in cancer-specific CD8 + T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE 2 -mediated inhibition of TCF1 + TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 + TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE 2 -EP 2 /EP 4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control., (© 2024. The Author(s).)

Type 1 conventional dendritic cells (cDC1) can support T cell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8 + T cell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1 + stem-like CD8 + T cells. We identify a distinct population of immunostimulatory CCR7 neg cDC1 that produce CXCL9 to promote cluster formation and cross-present tumor antigens within these niches, which is required for intratumoral CD8 + T cell differentiation and expansion and promotes cancer immune control. Similarly, in human cancers, CCR7 neg cDC1 interact with CD8 + T cells in clusters and are associated with patient survival. Our findings reveal an intratumoral phase of the anti-cancer T cell response orchestrated by tumor-residing cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Type 1 conventional dendritic cells (cDC1s) are critical for anti-cancer immunity. Protective anti-cancer immunity is thought to require cDC1s to sustain T cell responses within tumors, but it is poorly understood how this function is regulated and whether its subversion contributes to immune evasion. Here, we show that tumor-derived prostaglandin E2 (PGE 2 ) programmed a dysfunctional state in intratumoral cDC1s, disabling their ability to locally orchestrate anti-cancer CD8 + T cell responses. Mechanistically, cAMP signaling downstream of the PGE 2 -receptors EP2 and EP4 was responsible for the programming of cDC1 dysfunction, which depended on the loss of the transcription factor IRF8. Blockade of the PGE 2 -EP2/EP4-cDC1 axis prevented cDC1 dysfunction in tumors, locally reinvigorated anti-cancer CD8 + T cell responses, and achieved cancer immune control. In human cDC1s, PGE 2 -induced dysfunction is conserved and associated with poor cancer patient prognosis. Our findings reveal a cDC1-dependent intratumoral checkpoint for anti-cancer immunity that is targeted by PGE 2 for immune evasion., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)