Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity

Junyun Lai, Sherly Mardiana, Imran G. House, Kevin Sek, Melissa A. Henderson, Lauren Giuffrida, Amanda X.Y. Chen, Kirsten L. Todd, Emma V. Petley, Jack D. Chan, Emma M. Carrington, Andrew M. Lew, Benjamin J. Solomon, Joseph A. Trapani, Katherine Kedzierska, Maximilien Evrard, Stephin J. Vervoort, Jason Waithman, Phillip K. Darcy, Paul A. Beavis

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.

Original languageEnglish
Pages (from-to)914-926
Number of pages13
JournalNature Immunology
Volume21
Issue number8
DOIs
Publication statusPublished - 1 Aug 2020

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