Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity

SIMPLE SUMMARY: Poorly immunogenic head and neck squamous carcinomas (HNSCC) remain difficult to treat due to poor response rates to immunotherapy. Inhibition of the PI3K catalytic subunit p110γ, which is expressed in leukocytes and some HNSCCs, has shown promise in treating HNSCC; with clinical trials underway to gauge its effectiveness. However, the effect of PI3K p110γ inhibition on the host immune system in poorly immunogenic HNSCC has not been fully described. In this study, our group characterized the immune response to poorly immunogenic HNSCC in the absence of PI3K p110γ using an orthotopic mouse model with the MOC2 cell line. We found that mice lacking p110γ did not demonstrate significantly different tumor growth or metastasis, though we observed substantial elevation in both anti-tumor and immunosuppressive activity at the primary tumor site. Our results indicate that PI3K p110γ inhibition may potentially enhance anti-tumor immunity against poorly immunogenic HNSCC if administered with checkpoint inhibitors. ABSTRACT: HNSCC is the sixth most common cancer, with around 650,000 new cases yearly. Gain of function mutations in the PI3K pathway are common in HNSCC, and inhibition of the PI3K p110γ subunit has shown promise in HNSCC treatment. However, given that PI3K p110γ plays an important role in myeloid and lymphoid immune cell function, it is essential to understand how PI3K p110γ inhibition affects the anti-tumor immune response independent of tumor cells. To elucidate PI3K p110γ function in HNSCC, we employed an orthotopic mouse model using poorly immunogenic and aggressive cell line MOC2 on Pik3cg(−/−) mice. We observed that wild-type and Pik3cg(−/−) mice displayed similar rates of HNSCC tumor growth and metastasis after 20 days following tumor injection. T-cell infiltration and intrinsic T-cell responses to MOC2 oral tumors were comparable between wild-type and Pik3cg(−/−) mice. Interestingly, the immune response of tumor-bearing Pik3cg(−/−) mice was marked by increased anti-tumor cytotoxic molecules (IFN-γ, IL-17)) by T-cells and immune checkpoint marker (PD-L1, PD-1) expression by myeloid cells and T-cells compared to tumor-bearing wild-type mice. Taken together, our findings demonstrate that inhibition of PI3K p110γ modulates tumor-associated immune cells, which likely potentiates HNSCC treatment when used in combination with selective checkpoint inhibitors.