Flt3L-mediated tumor cDC1 expansion enhances immunotherapy by priming stem-like CD8+ T cells in lymph nodes

作者: Junyun Lai, Cheok Weng Chan, Jesse D. Armitage, Katherine M. Audsley, Yu-Kuan Huang, Emily B. Derrick, Laura S. Carstensen, Christina M. Scheffler, Matt E. Jones, Kevin Sek, Nicola Principe, Joelle S. Kim, Imran G. House, Amanda X. Y. Chen, Kah Min Yap, Jim Middelburg, Isabelle Munoz, Dat Nguyen, Junming Tong, Thang X. Hoang, Kirsten L. Todd, Maximilien Evrard, Jonathan Chee, Laura K. Mackay, Alistair R. R. Forrest, Ian A. Parish, Anthony Bosco, Jason Waithman, Paul A. Beavis & Phillip K. Darcy
杂志: Nature Immunology
Doi: https://www.doi.org/10.1038/s41590-026-02419-4
出版日期: 2026/2/10

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摘要

Immune checkpoint blockade (ICB) evokes antitumor immunity through the reinvigoration of T cell responses. T cell differentiation status controls response, with less differentiated cells having an enhanced capacity to proliferate after ICB. Given that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted T cells (TPEX), we hypothesized that expansion of cDC1s with Flt3L could enhance responses to ICB. Here we show that treatment with Fms-related tyrosine kinase 3 ligand (Flt3L) expands CD62L+SLAMF6+CD8+ T cells in the tumor through a mechanism that requires XCR1+ dendritic cells to traffic to the tumor-draining lymph node. The combination of Flt3L and anti-CTLA-4 enhanced therapeutic responses. Combination therapy is associated with the emergence of a CD8+ T cell subset characterized by the expression of Il21r and oligoclonal expansion of CD8+ T cells within tumors through a mechanism that is dependent on lymph node egress.

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