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

Sharanya K M Wijesinghe^#¹, Lisa Rausch^#¹, Sarah S Gabriel¹, Giovanni Galletti^{2

3}, Marco De Luca², Lei Qin¹, Lifen Wen¹, Carlson Tsui¹, Kevin Man¹, Leonie Heyden¹, Teisha Mason¹, Lewis D Newland^{1

4}, Andrew Kueh^{5

6

7

8}, Yang Liao^{6

7

9}, David Chisanga^{6

7}, Julian Swatler², Emanuele Voulaz^{2

10}, Giuseppe Marulli^{2

10}, Valentina Errico², Agnese Losurdo², Gustavo R Rossi¹¹, Fernando Souza-Fonseca-Guimaraes¹¹, Nicholas D Huntington^{9

12}, Thomas Gebhardt¹, Daniel T Utzschneider¹, Marco J Herold^{5

6

7

8}, Wei Shi^{6

7

9}, Jan Schroeder¹, Enrico Lugli², Axel Kallies^{13

14}

Affiliations

¹ Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia.
² IRCCS Humanitas Research Hospital, Rozzano, Italy.
³ School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, San Diego, CA, USA.
⁴ Institute of Experimental Oncology (IEO), Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
⁵ The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
⁶ Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.
⁷ School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia.
⁸ Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
⁹ Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
¹⁰ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
¹¹ Frazer Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia.
¹² oNKo-Innate, Melbourne, Victoria, Australia.
¹³ Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. axel.kallies@unimelb.edu.au.
¹⁴ Institute of Molecular Medicine & Experimental Immunology, University Hospital Bonn, Bonn, Germany. axel.kallies@unimelb.edu.au.

^# Contributed equally.

PMID: 40730900
DOI: 10.1038/s41590-025-02219-2

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

Sharanya K M Wijesinghe et al. Nat Immunol. 2025 Aug.

. 2025 Aug;26(8):1367-1383.

doi: 10.1038/s41590-025-02219-2. Epub 2025 Jul 29.

Authors

Affiliations

¹ Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia.
² IRCCS Humanitas Research Hospital, Rozzano, Italy.
³ School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, San Diego, CA, USA.
⁴ Institute of Experimental Oncology (IEO), Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
⁵ The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
⁶ Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.
⁷ School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia.
⁸ Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
⁹ Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
¹⁰ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
¹¹ Frazer Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia.
¹² oNKo-Innate, Melbourne, Victoria, Australia.
¹³ Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Queensland, Australia. axel.kallies@unimelb.edu.au.
¹⁴ Institute of Molecular Medicine & Experimental Immunology, University Hospital Bonn, Bonn, Germany. axel.kallies@unimelb.edu.au.

^# Contributed equally.

PMID: 40730900
DOI: 10.1038/s41590-025-02219-2

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: A.K. receives research support from Pfizer. N.D.H. is a founder and shareholder in oNKo-Innate and serves on advisory boards for Bristol Myers Squibb and Syena. T.G. was a scientific advisory board member of oNKo-Innate and received research funding from Merck Healthcare KGaA. E.L. is listed as the inventor on a patent on TSCM cells and received royalties related to that patent, received research funding from Bristol Myers Squibb on a topic unrelated to this paper and reports consulting fees from BD Biosciences, BioLegend, Swarm Oncology, Pfizer, Menarini and Astra Zeneca. All other authors declare no competing interests.

References

1. Philip, M. & Schietinger, A. CD8⁺ T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. 22, 209–223 (2022). - PubMed
1. Giles, J. R., Globig, A. M., Kaech, S. M. & Wherry, E. J. CD8⁺ T cells in the cancer-immunity cycle. Immunity 56, 2231–2253 (2023). - PubMed - PMC
1. Rausch, L. & Kallies, A. Molecular mechanisms governing CD8 T cell differentiation and checkpoint inhibitor response in cancer. Annu Rev. Immunol. 43, 515–543 (2025). - PubMed
1. Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016). - PubMed - PMC
1. Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8⁺ T cells sustain the immune response to chronic viral infections. Immunity 45, 415–427 (2016). - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials