Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity.
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
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
15
10
2019
accepted:
31
03
2020
pubmed:
20
5
2020
medline:
5
11
2020
entrez:
20
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32424363
doi: 10.1038/s41590-020-0676-7
pii: 10.1038/s41590-020-0676-7
doi:
Substances chimiques
Antigens, Neoplasm
0
Immunologic Factors
0
Membrane Proteins
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
flt3 ligand protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
914-926Commentaires et corrections
Type : CommentIn
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