Polymorphonuclear myeloid-derived suppressor cells and phosphatidylinositol-3 kinase gamma are critical to tobacco-mimicking oral carcinogenesis in mice

• Published in: Journal for immunotherapy of cancer Vol. 11; no. 9; p. e007110
• Main Authors: Nguyen, Khoa A, DePledge, Lisa N, Bian, Li, Ke, Yao, Samedi, Von, Berning, Amber A, Owens, Philip, Wang, Xiao-Jing, Young, Christian D
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.09.2023; BMJ Publishing Group
• Series: Original research
• Subjects: Animals; Basic Tumor Immunology; Blood tests; Cancer; Cancer therapies; Carcinogenesis; Carcinogens - toxicity; Carcinoma, Squamous Cell - chemically induced; Drinking water; Granulocytes; Head & neck cancer; Head and Neck Neoplasms; Histology; Human papillomavirus; Humans; Immunotherapy; Kinases; Medical prognosis; Mice; Mouth Neoplasms - chemically induced; Mutation; Myeloid-Derived Suppressor Cells; Nicotiana; Phosphatidylinositol 3-Kinase; Phosphatidylinositols; Quality of life; Squamous Cell Carcinoma of Head and Neck; Tobacco; Tongue; Tumors; head and neck neoplasms; drug evaluation, preclinical; tumor microenvironment; myeloid-derived suppressor cells
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-007110

Oral squamous cell carcinoma (OSCC) is a devastating disease most often associated with tobacco consumption that induces a field of mutations from which a tumor arises. Identification of ways to prevent the emergence of cancer in high-risk patients is an ultimate goal for combatting all types of cancer, including OSCC. Our study employs a mouse model of tongue carcinogenesis induced by tobacco carcinogen mimetic, 4-nitroquinoline 1-oxide (4NQO), to establish tongue dysplasia and OSCC. We use conventional histology, immunohistochemistry, multispectral imaging, mass cytometry, novel cell lines, pharmaceutical inhibition of PI3Kγ, T-cell suppression assays and mouse transplant models in our functional experimentation. In our study, we identify Ly6G+ granulocytes as the most abundant immune cell type in a model of tongue carcinogenesis induced by tobacco carcinogen mimetic 4NQO. Targeting Ly6G+ granulocytes with a pharmacologic inhibitor of PI3Kγ, an isoform of PI3K exclusively expressed by myeloid cells, resulted in reduced tongue dysplasia severity, and reduced rates of OSCC. Importantly, we performed functional assays with the Ly6G+ granulocytes induced in cell line models of 4NQO carcinogenesis to demonstrate that these granulocytes have increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activity against T-cell proliferation and these PMN-MDSCs play a functional role in promoting tumor formation by inhibiting tumor regression in a PI3Kγ-dependent manner. Overall, our data suggest that recruitment of PMN-MDSCs to sites of dysplasia is critical to immune suppression of CD8 T cells, thereby permitting malignancy, and PI3Kγ inhibitors are one mechanism to reduce PMN-MDSC recruitment, immunosuppression and tumorigenesis in OSCC.