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Abstract A86: PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion

Introduction: Tumor-associated macrophages promote immunosuppressive microenvironment in head and neck squamous cell carcinoma (HNSCC). We previously reported that macrophage PI3-kinase γ (PI3Kγ) controls a critical switch between immune stimulation and suppression during inflammation and cancer. The aim of the present study was to investigate the effect of PI3Kγ inhibition on T-cell immune response, especially on T-cell memory and exhaustion status using mouse models of HNSCC. Materials and Methods: Wild-type (WT) or Pik3cg-/- 6- to 8-week-old male syngeneic C57Bl/6J mice were implanted with HPV+ MEER tumor cells (mouse HPV+ HNSCC cell line) by subcutaneous injection. Tumors, draining lymph nodes and spleens were isolated, then analyzed using flow cytometry or mass cytometry. Mice that completely cleared tumors were reinjected with tumor cells and tumor growth was monitored. CD90.2+ T cells or CD19+ B cells that were harvested from spleens of WT or Pik3cg-/- tumor-inoculated mice were mixed 1:1 with viable tumor cells and injected into the flanks of naive WT mice. Results: Mice lacking PI3Kγ exhibited suppressed growth of implanted HPV+ MEER tumors. The proportion of T cells, especially CD8+ T cells, significantly increased in tumors from Pik3c-/- mice. T cells from Pik3cg-/- tumors expressed significantly more granzyme B and less T-cell exhaustion markers. The proportion of CD8+ effector memory T cells significantly increased in spleens from Pik3cg-/- mice. Mice that were implanted with both tumor cells and T cells from spleens of tumor-bearing Pik3cg-/- mice exhibited significant suppression of tumor growth. All mice that had previously cleared tumors dramatically suppressed tumor growth when rechallenged with tumor cells and remained cancer-free. Conclusion:Pik3cg-/- mice showed more activated T-cell immune response and T-cell memory than WT, resulting in significant suppression of tumor growth. These results suggest that PI3Kγ-targeted therapy might enhance the activity of checkpoint inhibitors through the activation of T-cell immune response in patients with HNSCC. Citation Format: Hideyuki Takahashi, Paulina Pathria, Ryan Shepard, Ann Shih, Tiani L. Louis, Judith A. Varner. PI3Kγ inhibition activates T cell memory and relieves T cell exhaustion [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A86.