RÉSUMÉ
Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5-9 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 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) 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 EP2/EP4 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 PGE2-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 PGE2-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
Sujet(s)
Lymphocytes T CD8+ , Prolifération cellulaire , Dinoprostone , Lymphocytes TIL , Tumeurs , Cellules souches , Échappement de la tumeur à la surveillance immunitaire , Animaux , Femelle , Humains , Mâle , Souris , Lymphocytes T CD8+/cytologie , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Différenciation cellulaire , Lignée cellulaire tumorale , Dinoprostone/métabolisme , Modèles animaux de maladie humaine , Facteur nucléaire hépatocytaire HNF-1 alpha/métabolisme , Interleukine-2 , Noeuds lymphatiques/cytologie , Noeuds lymphatiques/immunologie , Lymphocytes TIL/cytologie , Lymphocytes TIL/immunologie , Lymphocytes TIL/métabolisme , Souris de lignée C57BL , Tumeurs/immunologie , Tumeurs/prévention et contrôle , Sous-type EP2 des récepteurs des prostaglandines E/déficit , Sous-type EP2 des récepteurs des prostaglandines E/métabolisme , Sous-type EP4 des récepteurs des prostaglandines E/déficit , Sous-type EP4 des récepteurs des prostaglandines E/métabolisme , Transduction du signal , Cellules souches/cytologie , Cellules souches/immunologie , Cellules souches/métabolisme , Échappement de la tumeur à la surveillance immunitaire/immunologieRÉSUMÉ
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 CCR7neg 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, CCR7neg 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.