TLR5 Ligand-Secreting T Cells Reshape the Tumor Microenvironment and Enhance Antitumor Activity

Cancer Research
Degui GengEduardo Davila

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 chemoki...Continue Reading

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Citations

Feb 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Craig M BrackettAndrei V Gudkov
Nov 10, 2015·Molecular Oncology·Terhi Karpanen, Johanna Olweus
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Apr 16, 2021·Advanced Science·Xuehui HuangShaobing Zhou

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