Microbiota-induced plastic T cells enhance immune control of antigen-sharing tumors.
| Autor: | Najar TA; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA., Hao Y; Applied Bioinformatics Laboratories, Division of Advanced Research Technologies, New York, New York University School of Medicine, New York, NY 10016, USA.; Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA., Hao Y; Center for Genomics and Systems Biology, New York University, New York, NY 10003, USA.; New York Genome Center, New York, NY 10013, USA., Romero-Meza G; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.; Howard Hughes Medical Institute, New York, NY 10016, USA., Dolynuk A; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.; Howard Hughes Medical Institute, New York, NY 10016, USA., Littman DR; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.; Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.; Howard Hughes Medical Institute, New York, NY 10016, USA. |
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| Jazyk: | angličtina |
| Zdroj: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 14. Date of Electronic Publication: 2024 Aug 14. |
| DOI: | 10.1101/2024.08.12.607605 |
| Abstrakt: | Therapies that harness the immune system to target and eliminate tumor cells have revolutionized cancer care. Immune checkpoint blockade (ICB), which boosts the anti-tumor immune response by inhibiting negative regulators of T cell activation 1-3 , is remarkably successful in a subset of cancer patients, yet a significant proportion do not respond to treatment, emphasizing the need to understand factors influencing the therapeutic efficacy of ICB 4-9 . The gut microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, has emerged as a critical determinant of immune function and response to cancer immunotherapy, with multiple studies demonstrating association of microbiota composition with clinical response 10-16 . However, a mechanistic understanding of how gut commensal bacteria influence the efficacy of ICB remains elusive. Here we utilized a gut commensal microorganism, segmented filamentous bacteria (SFB), which induces an antigen-specific Th17 cell effector program 17 , to investigate how colonization with it affects the efficacy of ICB in restraining distal growth of tumors sharing antigen with SFB. We find that anti-PD-1 treatment effectively inhibits the growth of implanted SFB antigen-expressing melanoma only if mice are colonized with SFB. Through T cell receptor clonal lineage tracing, fate mapping, and peptide-MHC tetramer staining, we identify tumor-associated SFB-specific Th1-like cells derived from the homeostatic Th17 cells induced by SFB colonization in the small intestine lamina propria. These gut-educated ex-Th17 cells produce high levels of the pro-inflammatory cytokines IFN-γ and TNF-α, and promote expansion and effector functions of CD8 + tumor-infiltrating cytotoxic lymphocytes, thereby controlling tumor growth. A better understanding of how distinct intestinal commensal microbes can promote T cell plasticity-dependent responses against antigen-sharing tumors may allow for the design of novel cancer immunotherapeutic strategies. Competing Interests: Competing Interests: D.R.L. is cofounder of Vedanta Biosciences and ImmunAI, on the advisory boards of IMIDomics, Sonoma Biotherapeutics, and Evommune, and on the board of directors of Pfizer Inc. All other authors declare no competing interests. |
| Databáze: | MEDLINE |
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