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STAT1 inhibits T-cell exhaustion and myeloid derived suppressor cell accumulation to promote antitumor immune responses in head and neck squamous cell carcinoma.

ABSTRACT: Cancers of the oral cavity remain the sixth most diagnosed cancer worldwide, with high rates of recurrence and mortality. We determined the role of STAT1 during oral carcinogenesis using two orthotopic models in mice genetically deficient for Stat1. Metastatic (LY2) and nonmetastatic (B4B8) head and neck squamous cell carcinoma (HNSCC) cell lines were injected into the oral cavity of Stat1 deficient (Stat1^-/- ) and Stat1 competent (Stat1^+/+ ) mice. Stat1^-/- mice displayed increased tumor growth and metastasis compared to Stat1^+/+ mice. Mechanistically, Stat1^-/- mice displayed impaired CD4+ and CD8+ T-cell expansion compared to Stat1^+/+ mice. This was associated with enhanced T-cell exhaustion, and severely attenuated T-cell antitumor effector responses including reduced expression of IFN-? and perforin at the tumor site. Interestingly, tumor necrosis factor (TNF)-? production by T cells in tumor-bearing mice was suppressed by Stat1 deficiency. This deficiency in T-cell expansion and functional responses in mice was linked to PD-1 and CD69 overexpression in T cells of Stat1^-/- mice. In contrast, we observed increased accumulation of CD11b+ Ly6G+ myeloid derived suppressor cells in tumors, draining lymph nodes, spleens and bone marrow of tumor-bearing Stat1^-/- mice, resulting in a protumorigenic microenvironment. Our data demonstrates that STAT1 is an essential mediator of the antitumor response through inhibition of myeloid derived suppressor cell accumulation and promotion of T-cell mediated immune responses in murine head and neck squamous cell carcinoma. Selective induction of STAT1 phosphorylation in HNSCC patients could potentially improve oral tumor outcomes and response to therapy.

SUBMITTER: Ryan N

PROVIDER: S-EPMC7366342 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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STAT1 inhibits T-cell exhaustion and myeloid derived suppressor cell accumulation to promote antitumor immune responses in head and neck squamous cell carcinoma.

Ryan Nathan N Anderson Kelvin K Volpedo Greta G Hamza Omar O Varikuti Sanjay S Satoskar Abhay R AR Oghumu Steve S

International journal of cancer 20191129 6

Cancers of the oral cavity remain the sixth most diagnosed cancer worldwide, with high rates of recurrence and mortality. We determined the role of STAT1 during oral carcinogenesis using two orthotopic models in mice genetically deficient for Stat1. Metastatic (LY2) and nonmetastatic (B4B8) head and neck squamous cell carcinoma (HNSCC) cell lines were injected into the oral cavity of Stat1 deficient (Stat1-/- ) and Stat1 competent (Stat1+/+ ) mice. Stat1-/- mice ...[more]

PMID: 31709529

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Project description:BackgroundEcto-5'-nucleotidase (cluster of differentiation 73/CD73) is an ectonucleotidase that is being evaluated as a biomarker for the diagnosis and prognosis of various types of cancer. However, the clinicopathological relationship between CD73 expression in monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSC (PMN-MDSCs) in head and neck squamous cell carcinomas (HNSCCs) is not clear. Understanding the phenotypic and functional characteristics of human CD73+ MDSCs in the tumor microenvironment could help elucidate the roles of these cells in the ontogeny, spread, and treatment of solid cancer.MethodsIn the present study, we first analyzed the expression percentage of human M-MDSCs and PMN-MDSCs subsets circulating in peripheral blood of patients with head and neck tumors originated in nasopharynx, oropharynx, oropharynx and larynx. To identify the correlation between phenotypic characteristics of MDSCs and clinical stages in HNSCC, we extended the study by analyzing the percentage, CD73 phenotype and immunosuppressive function of MDSCs and the correlation with the clinical parameters. Moreover, we compare the functions of both M-MDSCs and PMN-MDSCs blunts T-cell function in an ectonucleotidase-dependent manner.ResultsOur study revealed that PMN-MDSCs were significantly increased in HNSCC patients, contributing to MDSC-mediated T cell immune suppression. Our results indicated that PMN-MDSCs comprised the majority of MDSCs participating in anticancer immunosuppression. The increase in PMN-MDSCs was directly correlated with the clinical stages of HNSCC. Levels of CD73 were increased in PMN-MDSCs and were correlated with the clinical stages of HNSCC. The ectonucleotidase inhibitor adenosine 5'-(α,β-methylene)diphosphate (APCP) decreased its suppression towards T cell proliferation. Ectonucleotidase inhibitors are promising candidates for the treatment of HNSCC.ConclusionsThese studies demonstrate the expansion of PMN-MDSCs correlated with expression of CD73 and increasing clinical stages in HNSCC. These CD73+ PMN-MDSCs contributes to T cell immune suppression activity in HNSCC patients. Using ectonucleotidase inhibitors is a promising rationale for PMN-MDSCs in future clinical development of immunotherapy in human HNSCC cancer.

Dataset Information

STAT1 inhibits T-cell exhaustion and myeloid derived suppressor cell accumulation to promote antitumor immune responses in head and neck squamous cell carcinoma.

Publications

STAT1 inhibits T-cell exhaustion and myeloid derived suppressor cell accumulation to promote antitumor immune responses in head and neck squamous cell carcinoma.

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