Enhanced AKT-dependent metabolic fitness and antitumor effect of T lymphocytes in lung cancer model

Introduction: PI3K signaling plays a pivotal role in balancing of immune responses. This study is to elucidate the role of PI3K-AKT signaling in regulating T cell metabolic fitness. Methods: PI3K/AKT inhibitors including BKM120 were used to evaluate the contribution of PI3K-AKT signaling on the metabolic fitness of T cell. Glucose metabolism and T cell activity were measured by flow cytometry, IHC, RT-PCR. Oxygen consumption rate (OCR) and extra cellular acidification rate (ECAR) were examined by seahorse. In addition, anti-tumor effects of T cells were evaluated by adaptive transfer in LLC2 tumor bearing mouse. Results: Compare to vehicle, BKM120-treated antigen-specific CD8 + T cells co-cultured with LLC2 cancer cells maintained cytotoxic effects under hypoglycemic and hypoxic conditions. Treatment of BKM120 significantly reduced tumor growth, compared to vehicle in syngeneic models (LLC2, KLN205), whereas it did not affect tumor growth in nude mice, which suggests role of activation of antitumor immunity, augmented by BKM120. Compared to vehicle, BKM120 significantly induced higher infiltration of CD8 + T cells and reduction of Foxp3 + regulatory T cell and CD11b + /Gr-1 + myeloid derived suppressor cells. Intriguingly, increased glucose uptake through overexpression of glucose transporter (GLUT1) was observed upon BKM120 treatment. Glut1 overexpression occurred through the release of feedback inhibition of mTORC2 followed by rebound AKT activation. In addition, glycolysis-related genes ( Glut1 , Hk, Pgam , Pdk and Pgm ) and OCR/ECAR were significantly augmented in BKM120/selective PI3K-delta inhibitor (Idelalisib)-treated group. The enhanced glycolysis via PI3K signaling inhibition was significantly more prominent by Idelalisib, compared to BKM120 or selective PI3K-alpha inhibitor (BYL-719). The antigen-specific T cells pretreated with BKM120 ex vivo exhibited substantially more potent antitumor effects, compared to untreated T cells, in LLC2 tumor-bearing nude mice. Conclusion: PI3K inhibitor, specifically selective PI3K-delta inhibitor, promotes AKT-dependent metabolic fitness of T cells which sustain anti-cancer effects under nutrient/oxygen-deprived tumor microenvironment. These data support a rationale for combination of selective PI3K-delta inhibitor with checkpoint inhibitors anti-PD1 for patient with Lung cancer. Citation Format: Sung Eum Kim, Kyoung-Ho Pyo, Sang Bin Lim, Mi Ran Yun, Jae Hwan Kim, Ji Min Lee, Ha Ni Jo, Chun-Feng Xin, Jae Seok Cho, Byoung Chul Cho. Enhanced AKT-dependent metabolic fitness and antitumor effect of T lymphocytes in lung cancer model [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 1098.