Abstract 1513: PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion through the reprogramming of tumor-associated macrophages

Abstract

We previously reported that macrophage PI3-kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ inhibition repolarizes tumor-associated macrophages, leading to downregulation of immune suppressive factors such as Arginase and IL10 and upregulation of IL12 and other pro-inflammatory cytokines. This results in recruitment and activation of intratumoral CD8+ T cells, as well as induction of immunological memory (Kaneda et al 2016). In the present study, we investigated the effect of PI3Kγ inhibition on T cell immune responses, including T cell memory induction and T cell exhaustion, in mouse models of head and neck squamous cell carcinomas (HNSCC). We found that Pik3cg−/− mice cleared implanted HPV+ HNSCC tumors; when re-challenged with tumor cells, these mice rapidly cleared secondary tumors and remained cancer-free. The proportion of T cells, especially CD8+ T cells, significantly increased in primary tumors from Pik3cg−/− mice. These CD8+ T cells expressed significantly more granzyme B and interferon and less T cell exhaustion markers than T cells from WT animals, indicating that PI3Kγ inhibition in macrophages results in T cell activation. We found that anti-tumor activity was transferable, as adoptive transfer of splenic T cells from Pik3cg−/− mice to naive WT mice suppressed tumor growth. Accordingly, Pik3cg−/− mice with primary or secondary tumors exhibited more splenic CD62L-CD44+ CD8+ effector memory T cells than WT mice. In summary, Pik3cg−/− mice exhibit a more activated T cell immune response and T cell memory than WT mice, resulting significant suppression of tumor growth. These results suggest that PI3Kγ-targeted therapy may activate durable T cell immune responses in patients with HNSCC. Citation Format: Hideyuki Takahashi, Paulina Pathria, Ann Shih, Ryan M. Shepard, Marc A. Paradise, Judith A. Varner. PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion through the reprogramming of tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1513.