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<p>CD8<sup>+</sup> T cell-mediated tumor control and efficacy of immune checkpoint blockade (ICB) are associated with both precursors of exhausted T (T<sub>PEX</sub>) 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<sup>+</sup> T<sub>PEX</sub> 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<sub>PEX</sub> cells residing in tdLNs sustained CD8<sup>+</sup> T cell infiltration into tumors and mediated ICB response. The cytokine TGFβ was the central factor that enforced residency of intratumoral CD8<sup>+</sup> T cells and limited the abundance of stem-like T<sub>PEX</sub> cells in tdLNs, thereby restraining tumor control. A similar network of TGFβ-constrained intratumoral and extratumoral CD8<sup>+</sup> T cells with precursor and residency characteristics was found in human cancer.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月29日

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  • Sharanya K. M. Wijesinghe,
  • Lisa Rausch,
  • Sarah S. Gabriel,
  • Giovanni Galletti,
  • Marco De Luca,
  • Lei Qin,
  • Lifen Wen,
  • Carlson Tsui,
  • Kevin Man,
  • Leonie Heyden,
  • Teisha Mason,
  • Lewis D. Newland,
  • Andrew Kueh,
  • Yang Liao,
  • David Chisanga,
  • Julian Swatler,
  • Emanuele Voulaz,
  • Giuseppe Marulli,
  • Valentina Errico,
  • Agnese Losurdo,
  • Gustavo R. Rossi,
  • Fernando Souza-Fonseca-Guimaraes,
  • Nicholas D. Huntington,
  • Thomas Gebhardt,
  • Daniel T. Utzschneider,
  • Marco J. Herold,
  • Wei Shi,
  • Jan Schroeder,
  • Enrico Lugli,
  • Axel Kallies

摘要

CD8+ T cell-mediated tumor control and efficacy of immune checkpoint blockade (ICB) are associated with both precursors of exhausted T (TPEX) 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+ TPEX 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 TPEX 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 TPEX 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.