Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion.

Autor:	Gong W; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA.; University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA., Donnelly CR; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA., Heath BR; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA.; University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.; Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA., Bellile E; Department of Biostatistics, University of Michigan Health System, Ann Arbor, Michigan, USA., Donnelly LA; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA.; Division of Craniofacial and Surgical Services, University of North Carolina Adams School of Dentistry, Chapel Hill, North Carolina, USA., Taner HF; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA., Broses L; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA., Brenner JC; University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.; Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA., Chinn SB; University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.; Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA., Ji RR; Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA., Wen H; Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA., Nör JE; University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.; Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.; Department of Cariology, Restorative Science and Endodontics, University of Michigan, Ann Arbor, MI, USA., Wang J; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA., Wolf GT; University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.; Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA., Xie Y; Department of Computational Mathematics, Science, and Engineering, Michigan State University, East Lansing, Michigan, USA., Lei YL; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA.; University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.; Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.; Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2021 Nov 13; Vol. 10 (1), pp. 1997385. Date of Electronic Publication: 2021 Nov 13 (Print Publication: 2021).
DOI:	10.1080/2162402X.2021.1997385
Abstrakt:	Type-I interferon (IFN-I) signaling is critical to maintaining antigen-presenting cell function for anti-tumor immunity. However, recent studies have suggested that IFN-I signaling may also contribute to more aggressive phenotypes, raising the possibility that IFN-I downstream signaling in cancer and myeloid cells may exert dichotomous functions.We analyzed the clinicopathologic correlation of cancer-specific IFN-I activation in 195 head and neck squamous cell carcinoma patients. We also characterized the immune impact of IFN-I receptor (IFNAR1)-deficiency in syngeneic tumor models using biochemistry, flow cytometry, and single-cell RNA-Seq. We stained HNSCC tissue microarrays with a sensitive IFN-I downstream signaling activation marker, MX1, and quantitated cancer cell-specific MX1 staining. Kaplan-Meier analysis revealed that MX1-high tumors exhibited worse survival, a phenotype that depends on the number of CD8 + intratumoral T-cells. We found that cancer-specific IFNAR1 engagement promotes cancer stemness and higher expression levels of suppressive immune checkpoint receptor ligands in cancer-derived exosomes. Notably, mice bearing Ifnar1 -deficient tumors exhibited lower tumor burden, increased T-cell infiltration, reduced exhausted CD4 + PD1 high T-cells, and increased effector population CD8 + IFN-γ + T-cells. Then, we performed single-cell RNA-sequencing and discovered that cancer-specific IFN-I signaling not only restricts effector cells expansion but also dampens their functional fitness.The beneficial role of IFN-I activation is largely dependent on the myeloid compartment. Cancer-specific IFN-I receptor engagement promotes cancer stemness and the release of cancer-derived exosomes with high expression levels of immune checkpoint receptor ligands. Cancer-specific IFN-I activation is associated with poor immunogenicity and worse clinical outcomes in HNSCC. Competing Interests: Y.L.L. licensed the NOOC1 model to Kerafast Inc. Y.L.L. is a co-founder and serves on the Scientific Advisory Board for Saros Therapeutics. The other authors declare no conflict of interest relevant to the current study. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)
Databáze:	MEDLINE
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