Junyun Lai, Cheok Weng Chan, Jesse Armitage, Katherine M. Audsley, Yukuan Huang, Emily B. Derrick, Laura Stentoft Carstensen, C. Scheffler, Matt 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
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. Conventional type 1 dendritic cells (cDC1) can boost the precursor exhausted T cell population thought to be essential for efficacy of immune checkpoint therapy. Here the authors enhance this cellular network using Flt3L to expand cDC1s and then map the movement of T cells and DCs between tumors and lymph nodes.