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

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 an...

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Autores principales:	Wang Gong, Christopher R. Donnelly, Blake R. Heath, Emily Bellile, Lorenza A. Donnelly, Hülya F. Taner, Luke Broses, J. Chad Brenner, Steven B. Chinn, Ru-Rong Ji, Haitao Wen, Jacques E. Nör, Jie Wang, Gregory T. Wolf, Yuying Xie, Yu Leo Lei
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	type-i interferon head and neck cancer sting1 ifnar1 stemness Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/3c05d666229047cd81e16226c283d889
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spelling	oai:doaj.org-article:3c05d666229047cd81e16226c283d8892021-11-26T11:19:49ZCancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion2162-402X10.1080/2162402X.2021.1997385https://doaj.org/article/3c05d666229047cd81e16226c283d8892021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/2162402X.2021.1997385https://doaj.org/toc/2162-402XType-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+PD1high 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.Wang GongChristopher R. DonnellyBlake R. HeathEmily BellileLorenza A. DonnellyHülya F. TanerLuke BrosesJ. Chad BrennerSteven B. ChinnRu-Rong JiHaitao WenJacques E. NörJie WangGregory T. WolfYuying XieYu Leo LeiTaylor & Francis Grouparticletype-i interferonhead and neck cancersting1ifnar1stemnessImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncoImmunology, Vol 10, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	type-i interferon head and neck cancer sting1 ifnar1 stemness Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	type-i interferon head and neck cancer sting1 ifnar1 stemness Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Wang Gong Christopher R. Donnelly Blake R. Heath Emily Bellile Lorenza A. Donnelly Hülya F. Taner Luke Broses J. Chad Brenner Steven B. Chinn Ru-Rong Ji Haitao Wen Jacques E. Nör Jie Wang Gregory T. Wolf Yuying Xie Yu Leo Lei Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion
description	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+PD1high 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.
format	article
author	Wang Gong Christopher R. Donnelly Blake R. Heath Emily Bellile Lorenza A. Donnelly Hülya F. Taner Luke Broses J. Chad Brenner Steven B. Chinn Ru-Rong Ji Haitao Wen Jacques E. Nör Jie Wang Gregory T. Wolf Yuying Xie Yu Leo Lei
author_facet	Wang Gong Christopher R. Donnelly Blake R. Heath Emily Bellile Lorenza A. Donnelly Hülya F. Taner Luke Broses J. Chad Brenner Steven B. Chinn Ru-Rong Ji Haitao Wen Jacques E. Nör Jie Wang Gregory T. Wolf Yuying Xie Yu Leo Lei
author_sort	Wang Gong
title	Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion
title_short	Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion
title_full	Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion
title_fullStr	Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion
title_full_unstemmed	Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion
title_sort	cancer-specific type-i interferon receptor signaling promotes cancer stemness and effector cd8+ t-cell exhaustion
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/3c05d666229047cd81e16226c283d889
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Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion

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