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

Lai, J; Chan, CW; Armitage, JD; Audsley, KM; Huang, YK; Derrick, EB; Carstensen, LS; Scheffler, CM; Jones, ME; Sek, K; Principe, N; Kim, JS; House, IG; Chen, AXY; Yap, KM; Middelburg, J; Munoz, I; Nguyen, D; Tong, J; Hoang, TX; Todd, KL; Evrard, M; Chee, J; Mackay, LK; Forrest, ARR; Parish, IA; Bosco, A; Waithman, J; Beavis, PA; Darcy, PK

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

Author(s): Lai, J; Chan, CW; Armitage, JD; Audsley, KM; Huang, YK; Derrick, EB; Carstensen, LS; Scheffler, CM; Jones, ME; Sek, K; Principe, N; Kim, JS; House, IG; Chen, AXY; Yap, KM; Middelburg, J; Munoz, I; Nguyen, D; Tong, J; Hoang, TX; Todd, KL; Evrard, M; Chee, J; Mackay, LK; Forrest, ARR; Parish, IA; Bosco, A; Waithman, J; Beavis, PA; Darcy, PK;
Details: Publication Year 2026-03,Volume 27,Issue #3,Page 530-542
Journal Title: Nature Immunology
Publication Type: Research article
Abstract: 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(PEX)), 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.
Publisher: Springer Nature
Keywords: Animals; *CD8-Positive T-Lymphocytes/immunology; *Lymph Nodes/immunology; *Dendritic Cells/immunology; Mice; *Membrane Proteins/immunology/metabolism; Mice, Inbred C57BL; *Immunotherapy/methods; Immune Checkpoint Inhibitors/pharmacology/therapeutic use; Cell Line, Tumor; Humans; CTLA-4 Antigen/antagonists & inhibitors/immunology
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41590-026-02419-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41590-026-02419-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-02-24 05:56:04

Last Modified: 2026-03-26 03:00:02