Lymph-node-derived stem-like but not tumor-tissue-resident CD8(+) T cells fuel anticancer immunity

Wijesinghe, SKM; Rausch, L; Gabriel, SS; Galletti, G; De Luca, M; Qin, L; Wen, L; Tsui, C; Man, K; Heyden, L; Mason, T; Newland, LD; Kueh, A; Liao, Y; Chisanga, D; Swatler, J; Voulaz, E; Marulli, G; Errico, V; Losurdo, A; Rossi, GR; Souza-Fonseca-Guimaraes, F; Huntington, ND; Gebhardt, T; Utzschneider, DT; Herold, MJ; Shi, W; Schroeder, J; Lugli, E; Kallies, A

Author(s): Wijesinghe, SKM; Rausch, L; Gabriel, SS; Galletti, G; De Luca, M; Qin, L; Wen, L; Tsui, C; Man, K; Heyden, L; Mason, T; Newland, LD; Kueh, A; Liao, Y; Chisanga, D; Swatler, J; Voulaz, E; Marulli, G; Errico, V; Losurdo, A; Rossi, GR; Souza-Fonseca-Guimaraes, F; Huntington, ND; Gebhardt, T; Utzschneider, DT; Herold, MJ; Shi, W; Schroeder, J; Lugli, E; Kallies, A;
Details: Publication Year 2025-08,Volume 26,Issue #8,Page 1367-1383
Journal Title: Nature Immunology
Abstract: CD8(+) T cell-mediated tumor control and efficacy of immune checkpoint blockade (ICB) are associated with both precursors of exhausted T (T(PEX)) cells and tissue-resident memory T cells. Their relationships and relative contribution to tumor control, however, are insufficiently understood. Using single-cell RNA sequencing and genetic mouse models, we systematically dissected the heterogeneity and function of cytotoxic T cells in tumors and tumor-draining lymph nodes (tdLNs). We found that intratumoral TCF1(+) T(PEX) cells and their progeny acquired a tissue-residency program that limits their contribution to tumor control and ICB response. By contrast, MYB-dependent stem-like T(PEX) cells residing in tdLNs sustained CD8(+) T cell infiltration into tumors and mediated ICB response. The cytokine TGFβ was the central factor that enforced residency of intratumoral CD8(+) T cells and limited the abundance of stem-like T(PEX) cells in tdLNs, thereby restraining tumor control. A similar network of TGFβ-constrained intratumoral and extratumoral CD8(+) T cells with precursor and residency characteristics was found in human cancer.
Publisher: Springer Nature
Keywords: Animals; *Lymph Nodes/immunology; Mice; *CD8-Positive T-Lymphocytes/immunology; Transforming Growth Factor beta/metabolism; Mice, Inbred C57BL; *Neoplasms/immunology; *Lymphocytes, Tumor-Infiltrating/immunology; Humans; Immune Checkpoint Inhibitors/pharmacology
Research Division(s): Blood Cells and Blood Cancer
PubMed ID: 40730900
Publisher's Version: https://doi.org/10.1038/s41590-025-02219-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-08-08 03:14:13

Last Modified: 2025-08-08 03:14:30