PGE 2 limits effector expansion of tumour-infiltrating stem-like CD8 + T cells

• Published in: Nature (London) 2024-05, Vol.629 (8011), p.417
• Main Authors: Lacher, Sebastian B, Dörr, Janina, de Almeida, Gustavo P, Hönninger, Julian, Bayerl, Felix, Hirschberger, Anna, Pedde, Anna-Marie, Meiser, Philippa, Ramsauer, Lukas, Rudolph, Thomas J, Spranger, Nadine, Morotti, Matteo, Grimm, Alizee J, Jarosch, Sebastian, Oner, Arman, Gregor, Lisa, Lesch, Stefanie, Michaelides, Stefanos, Fertig, Luisa, Briukhovetska, Daria, Majed, Lina, Stock, Sophia, Busch, Dirk H, Buchholz, Veit R, Knolle, Percy A, Zehn, Dietmar, Dangaj Laniti, Denarda, Kobold, Sebastian, Böttcher, Jan P
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Dinoprostone - metabolism; Disease Models, Animal; Female; Hepatocyte Nuclear Factor 1-alpha - metabolism; Humans; Interleukin-2; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymphocytes, Tumor-Infiltrating - cytology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Mice; Mice, Inbred C57BL; Neoplasms - immunology; Neoplasms - prevention & control; Receptors, Prostaglandin E, EP2 Subtype - deficiency; Receptors, Prostaglandin E, EP2 Subtype - metabolism; Receptors, Prostaglandin E, EP4 Subtype - deficiency; Receptors, Prostaglandin E, EP4 Subtype - metabolism; Signal Transduction; Stem Cells - cytology; Stem Cells - immunology; Stem Cells - metabolism; Tumor Escape - immunology
• ISSN: 1476-4687

Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation ; however, this response is dysfunctional in tumours. Current cancer immunotherapies 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 ) restricts the proliferative expansion and effector differentiation of TCF1 CD8 T cells within tumours, which promotes cancer immune escape. PGE does not affect the priming of TCF1 CD8 T cells in draining lymph nodes. PGE acts through EP and EP (EP /EP ) 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 /EP 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 -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 -EP /EP axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.