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

• Published in: International journal of cancer 2020-03, Vol.146 (6), p.1717-1729
• Main Authors: Ryan, Nathan, Anderson, Kelvin, Volpedo, Greta, Hamza, Omar, Varikuti, Sanjay, Satoskar, Abhay R., Oghumu, Steve
• Format: Article
• Language: English
• Subjects: Accumulation; Animal models; Animals; Antitumor activity; Bone marrow; Bone tumors; Cancer; Carcinogenesis; CD11b antigen; CD4 antigen; CD69 antigen; CD8 antigen; Cell Line, Tumor; cytokine; Disease Models, Animal; Disease Progression; Exhaustion; Female; Head & neck cancer; Humans; Immunomodulation; Interferon; Lymph nodes; Lymph Nodes - pathology; Lymphocytes; Lymphocytes T; Male; Medical research; Metastases; Mice; Mice, Knockout; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Neoplasm Metastasis; Neoplasm Staging; oral; Oral cancer; Oral cavity; Perforin; Phosphorylation; signal; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - etiology; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Stat1 protein; STAT1 Transcription Factor - deficiency; STAT1 Transcription Factor - metabolism; Suppressor cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; transducer; Tumor cell lines; Tumor Microenvironment; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32781

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‐γ and perforin at the tumor site. Interestingly, tumor necrosis factor (TNF)‐α 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. What's new? STAT1 acts as both an oncogene and a tumor suppressor in head and neck squamous cell carcinoma. Whether expression by tumor cells or the tumor microenvironment influences STAT1 function remains unclear, however. This study identifies a novel role for STAT1 expressed by cells of the tumor microenvironment in host immune responses. In metastatic and non‐metastatic oral cancer cells in immunocompetent BALB/c mice, STAT1 suppresses T cell exhaustion, promotes TNF‐α production in T cells, and inhibits accumulation of myeloid‐derived suppressor cells. Induction of STAT1 signaling in immune cells within the oral tumor microenvironment could potentially improve head and neck tumor outcomes.