Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity
| Autor: | Junyun Lai, Maximilien Evrard, Lauren Giuffrida, Emma V. Petley, Katherine Kedzierska, Stephin J. Vervoort, Paul A. Beavis, Joseph A. Trapani, Imran G House, Kirsten L. Todd, Jason Waithman, Jack D Chan, Sherly Mardiana, Emma M. Carrington, Kevin Sek, Phillip K. Darcy, Benjamin Solomon, Melissa A. Henderson, Andrew M. Lew, Amanda X. Y. Chen |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
T-Lymphocytes T cell medicine.medical_treatment Immunology Receptors Antigen T-Cell Mice Transgenic Lymphocyte Activation Immunotherapy Adoptive Cell therapy Mice 03 medical and health sciences 0302 clinical medicine Antigen Antigens Neoplasm medicine Animals Humans Immunologic Factors Immunology and Allergy Receptors Chimeric Antigen Chemistry Membrane Proteins Dendritic Cells Neoplasms Experimental Dendritic cell Immunotherapy Chimeric antigen receptor Tumor antigen Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Cancer research Chimeric Antigen Receptor T-Cell Therapy 030215 immunology |
| Zdroj: | Nature Immunology. 21:914-926 |
| ISSN: | 1529-2916 1529-2908 |
| DOI: | 10.1038/s41590-020-0676-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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