口腔鳞状细胞癌(OSCC)是一种毁灭性疾病，最常与烟草消费相关，引发了突变场，并导致肿瘤的形成。确定防止高风险患者患癌的方法是战胜包括OSCC在内的癌症的终极目标。我们的研究利用以烟草致癌物模拟物4-硝基喹啉1-氧化物（4NQO）引发的小鼠舌癌模型，建立了舌部异形和OSCC。我们在功能实验中使用常规组织学、免疫组织化学、多光谱成像、质谱流式细胞术、新型细胞系、PI3Kγ药物抑制、T细胞抑制试验和小鼠移植模型。在我们的研究中，我们发现Ly6G+嗜中性粒细胞是由烟草致癌物模拟物4NQO引发的舌癌模型中最丰富的免疫细胞类型。用PI3Kγ的药物抑制剂靶向Ly6G+嗜中性粒细胞，这是仅由髓系细胞专属表达的PI3K亚型，导致舌部异形严重程度减轻，并减少OSCC的发病率。重要的是，我们在4NQO致癌模型细胞系中进行了Ly6G+嗜中性粒细胞的功能实验，证明这些嗜中性粒细胞对T细胞增殖具有增强的多形核巨噬细胞抑制活性（PMN-MDSC），而且这些PMN-MDSC在PI3Kγ依赖性的方式下通过抑制肿瘤回归在促进肿瘤形成中扮演功能性角色。总的来说，我们的数据表明，PMN-MDSC的招募对于免疫抑制CD8T细胞在异形部位至关重要，从而促进恶性肿瘤的形成，并且PI3Kγ抑制剂是减少PMN-MDSC招募、免疫抑制和OSCC肿瘤发生的一种机制。©作者（或其雇主）2023。在CC BY-NC许可下允许再利用。不允许商业再利用。详见权利和权限。BMJ出版。

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.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.