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

Nat Immunol. 2020 Aug;21(8):914-926. doi: 10.1038/s41590-020-0676-7. Epub 2020 May 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Dendritic Cells / immunology*
  • Humans
  • Immunologic Factors
  • Immunotherapy, Adoptive*
  • Lymphocyte Activation / immunology
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms, Experimental / immunology*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Chimeric Antigen / immunology
  • T-Lymphocytes / immunology*

Substances

  • Antigens, Neoplasm
  • Immunologic Factors
  • Membrane Proteins
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • flt3 ligand protein