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<p>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 (T<sub>PEX</sub>), 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<sup>+</sup>SLAMF6<sup>+</sup>CD8<sup>+</sup> T cells in the tumor through a mechanism that requires XCR1<sup>+</sup> 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<sup>+</sup> T cell subset characterized by the expression of <i>Il21r</i> and oligoclonal expansion of CD8<sup>+</sup> T cells within tumors through a mechanism that is dependent on lymph node egress.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月10日

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  • 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

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.