Abstract 1077: Macrophage PI3Kγ controls T cell activation and T cell memory generation through the production of IL-12

Abstract

Abstract We previously reported that macrophage PI3kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ inhibition polarizes tumor-associated macrophages (TAMs) into pro-inflammatory macrophages, leading to the recruitment and activation of intratumoral CD8+ T cells, tumor growth inhibition and anti-tumor memory (Kaneda et al 2016). In the present study, we elucidated the role of PI3Kγ in the control of T cell immune responses, including activation, memory generation and exhaustion, in mouse models of head and neck squamous cell carcinomas (HNSCC). High-dimensional single-cell analysis including single-cell RNA sequencing and mass cytometry of HPV+ HNSCC tumors revealed significant differences in intratumoral immune cell clusters in HPV+ HNSCC tumors from WT and Pik3cg−/− mice. Primary tumors from Pik3cg−/− mice exhibited more pro-inflammatory TAMs, more activated CD8+ T cells and fewer exhausted T cells than in tumors from WT mice. Both tumor- and spleen-derived T cells from Pik3cg−/− mice exhibited more IFNγ expression than those from WT mice; this increase could be reversed by the neutralization of IL-12 and MHCII. We observed significantly more effector memory T cells in spleens of Pik3cg−/− mice than WT mice; accordingly, adoptive transfer of Pik3cg−/− but not WT splenic T cells conferred tumor resistance onto naive WT mice, indicating that PI3Kγ inhibition promotes T cell mediated immunological memory. In summary, Pik3cg−/− mice exhibited more activated T cells, T cell mediated immune responses and T cell memory than WT mice, resulting significant and sustained suppression of tumor growth. These results indicate that PI3Kγ-targeted therapy may activate durable T cell immune responses in patients with HNSCC. Citation Format: Hideyuki Takahashi, Ryan M. Shepard, Marc A. Paradise, Sang Min Lee, Ann Shih, Cristina Flores-Arenas, William Kim, Judith A. Varner. Macrophage PI3Kγ controls T cell activation and T cell memory generation through the production of IL-12 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1077.