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- W4313408058 abstract "Abstract We previously demonstrated that anti-PD-1 antibody mediated activation of type 17 T-cells undermined checkpoint inhibitor therapy in the LSLKrasG12D murine lung cancer model. In this study we confirm that the Th17 subset is the primary driver of resistance to anti-PD-1; demonstrate that the ontogeny of dysplasia-associated Th17 cells is driven by microbiota-conditioned macrophages; and identify IL-17-COX-2/Prostoglandin E2 (PGE2) axis as the mediator of CD8+ cytotoxic T-lymphocyte (CTL) de-sensitization to checkpoint inhibitor therapy. Specifically, anti-PD-1 treatment of CD4+ T-cell RORc-deficient LSLKrasG12D mice resulted in a 50% increase in CTL cytotoxicity and a 2.2-fold reduction in tumor burden confirming the critical role of Th17 cells in resistance to therapy. Lung-specific depletion of microbiota reduced Th17 cell prevalence and tumor burden by ~2 and ~1.5 fold, respectively, establishing a link between microbiota and the Th17-driven tumorigenesis. Importantly, interstitial macrophages from microbiota sufficient, but not from microbiota-deficient, mice polarized naïve CD4+ T-cells towards a Th17 phenotype, highlighting their role in bridging microbiota and lung Th17 immunity. Neutralization of IL-17 diminished COX-2/PGE2 levels, whereas inhibition of COX-2 rescued CTL activity and restored tumor suppression in anti-PD-1 antibody-treated mice, revealing the molecular basis of IL-17-driven anti-PD-1 resistance. The clinical implications of these findings are discussed. Supported by grant from DOD grant (to N.E., OGMB190737) and in part through the NIH/NIGMS P20-GM135004 (1P20GM135005-01)" @default.
- W4313408058 created "2023-01-06" @default.
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- W4313408058 date "2022-05-01" @default.
- W4313408058 modified "2023-09-25" @default.
- W4313408058 title "Resistance to Anti-PD-1 Therapy is mediated via the Microbiota-Th17-Prostoglandin E2 Axis in the LSLKrasG12D Lung Cancer Model" @default.
- W4313408058 doi "https://doi.org/10.4049/jimmunol.208.supp.120.06" @default.
- W4313408058 hasPublicationYear "2022" @default.
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