Abstract 3790: Combined inhibition of myeloid cell PI3Kγ and regulatory T cell integrin αvβ8 promotes durable tumor suppression

Abstract The immunosuppressive tumor microenvironment (TME) remains a critical barrier to effective immunotherapy. Immune suppressive myeloid cells and regulatory T cells can each prevent effective anti-tumor immune responses. The integrin αvβ8 promotes immune evasion by serving as a key activator of latent TGF-β in regulatory T cells, while the lipid kinase PI3Kγ promotes immunosuppressive signaling in myeloid cells. Genetic and pharmacological inhibition of PI3Kγ stimulates integrin αvβ8 expression on regulatory T cells both in mouse models of cancer and in patients enrolled in cancer clinical trials. Inhibition of either αvβ8 or PI3Kγ significantly suppressed head and neck tumor growth, suggesting they each play important roles in modulating anti-tumor immunity. To gain mechanistic insights into the impacts of these therapeutic approaches, we performed single-cell RNA sequencing (scRNA-seq) on HPV+ HNSCC tumors from wild-type (WT) and PI3Kγ knockout (KO) mice, with or without anti-αvβ8 treatment, to investigate the individual and combined impacts of PI3Kγ inhibition and αvβ8 blockade in the TME. RNA velocity and cell-cell communication inference analysis was performed to uncover dynamic regulatory interactions among cell populations. Antagonism of integrin αvβ8 led to increased CD8+ T cell infiltration and a reduction in TGF-β-responsive transcriptional programs. PI3Kγ inhibition promoted a proinflammatory shift in myeloid cells, characterized by diminished M2-like polarization and enhanced antigen presentation, and increased CD8+ T cell recruitment. Together combined inhibition of αvβ8 and PI3Kγ reversed T cell exclusion and promoted durable tumor suppression. Citation Format: Erpei Wang, Giuliana Mognol, MOHAMMAD AMJAD, Hui Chen, Mark Paradise, Dean Sheppard, judith Varner. Combined inhibition of myeloid cell PI3Kγ and regulatory T cell integrin αvβ8 promotes durable tumor suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3790.