Antigen reactivity defines tissue-resident memory and exhausted T cells in tumors

Burn, TN; Schr&#246;der, J; Gandolfo, LC; Osman, M; Wainwright, EN; Lam, EYN; McDonald, KM; Evans, RB; Li, S; Rawlinson, D; Dryburgh, L; Zaid, A; Maliga, Z; Schienstock, D; Meiser, P; Lee, HJ; Lai, H; Moreira, ML; Zareie, P; Lee, LH; Huq, L; Christo, SN; Seow, JJW; Ching, KA; Guillaume, SM; Knezevic, K; Park, SL; Evrard, M; Waithman, J; Gebhardt, T; Mueller, SN; Riddiough, GE; Perini, MV; Tsao, SCH; Speed, TP; Sorger, PK; Loi, S; Carbone, FR; Gras, S; Fisher, TS; Baaten, BJ; Dawson, MA; Mackay, LK

Antigen reactivity defines tissue-resident memory and exhausted T cells in tumors

Author(s): Burn, TN; Schröder, J; Gandolfo, LC; Osman, M; Wainwright, EN; Lam, EYN; McDonald, KM; Evans, RB; Li, S; Rawlinson, D; Dryburgh, L; Zaid, A; Maliga, Z; Schienstock, D; Meiser, P; Lee, HJ; Lai, H; Moreira, ML; Zareie, P; Lee, LH; Huq, L; Christo, SN; Seow, JJW; Ching, KA; Guillaume, SM; Knezevic, K; Park, SL; Evrard, M; Waithman, J; Gebhardt, T; Mueller, SN; Riddiough, GE; Perini, MV; Tsao, SCH; Speed, TP; Sorger, PK; Loi, S; Carbone, FR; Gras, S; Fisher, TS; Baaten, BJ; Dawson, MA; Mackay, LK;
Details: Publication Year 2026-01,Volume 27,Issue #1,Page 98-109
Journal Title: Nature Immunology
Publication Type: Research article
Abstract: CD8(+) T cells are an important weapon in the therapeutic armamentarium against cancer. While CD8(+)CD103(+) T cells with a tissue-resident memory T (T(RM)) cell phenotype are associated with favorable prognoses, the tumor microenvironment also contains dysfunctional exhausted T (T(EX)) cells that exhibit a variety of T(RM)-like features. Here we deconvolute T(RM) and T(EX) cells across human cancers, ascribing markers and gene signatures that distinguish these populations and enable their functional distinction. Although T(RM) cells have superior functionality and are associated with long-term survival post-tumor resection, they are not associated with responsiveness to immune checkpoint blockade. Tumor-associated T(EX) and T(RM) cells are clonally distinct, with the latter comprising tumor-independent bystanders and tumor-specific cells segregated from cognate antigen. Intratumoral T(RM) cells can be forced toward an exhausted fate when chronic antigen stimulation occurs, indicating that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between tumor-associated T(EX) and T(RM) populations. These results highlight unique functions for T(RM) and T(EX) cells in tumor control, underscoring the need for distinct strategies to harness these populations for cancer therapies.
Publisher: Springer Nature
Keywords: Humans; Tumor Microenvironment/immunology; *Neoplasms/immunology; *Immunologic Memory; *CD8-Positive T-Lymphocytes/immunology; *Antigens, Neoplasm/immunology; *Lymphocytes, Tumor-Infiltrating/immunology; *Memory T Cells/immunology; Animals; Mice
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41590-025-02347-9
Open Access at Publisher's Site: https://doi.org/10.1038/s41590-025-02347-9
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-20 12:06:13

Last Modified: 2026-01-20 12:06:31