title: TLR5 Ligand-Secreting T Cells Reshape the Tumor Microenvironment and Enhance Antitumor Activity.
abstract: The tumor microenvironment counters antitumor T-cell responses, in part, by blunting their activation and infiltration. Ligands that engage Toll-like receptors (TLR) on T cells and antigen-presenting cells can act as potent immune adjuvants. In this study, we show how tumor-reactive T cells engineered to secrete bacterial flagellin, a TLR5 ligand (TLR5L), can engender a costimulatory signal that augments antitumor activity. Human T cells engineered to express TLR5L along with DMF5, a T-cell receptor that recognizes the melanoma antigen MART-127-35 (DMF5(TLR5L) T cells), displayed increased proliferation, cytokine production, and cytolytic activity against melanoma cells. In a xenogenetic model, adoptive transfer of DMF5(TLR5L) T cells reduced tumor growth kinetics and prolonged mouse survival. In a syngeneic model, similarly engineered melanoma-reactive T cells (pmel(TLR5L)) displayed a relative increase in antitumor activity against established tumors, compared with unmodified T cells. In this model, we documented increased T-cell infiltration associated with increased levels of CCR1 and CXCR3 levels on T cells, a reduction in PD-1(+)Lag3(+) T cells and CD11(+)Gr1(+) myeloid-derived suppressor cells, and changes in the chemokine/cytokine profile of tumors. Our findings show how T cell-mediated delivery of a TLR agonist to the tumor site can contribute to antitumor efficacy, in the context of adoptive T-cell immunotherapy.
authors: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, 21201.
authors: Degui
authors: D
authors: Geng
authors: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, 21201.
authors: Sabina
authors: S
authors: Kaczanowska
authors: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, 21201.
authors: Alexander
authors: A
authors: Tsai
authors: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, 21201.
authors: Kenisha
authors: K
authors: Younger
authors: Louisiana State University Health Sciences Center, New Orleans, Louisiana, 70112.
authors: Augusto
authors: A
authors: Ochoa
authors: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, 21201.
authors: Aaron P
authors: AP
authors: Rapoport
authors: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250.
authors: Sue
authors: S
authors: Ostrand-Rosenberg
authors: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, 21201.|Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, 21201.
authors: Eduardo
authors: E
authors: Davila
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005408:Flagellin / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000819:agonists / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011994:Recombinant Proteins; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin