PI3Kα inhibitor GNE-493 triggers antitumor immunity in murine lung cancer by inducing immunogenic cell death and activating T cells

• Published in: International immunopharmacology 2024-03, Vol.130, p.111747-111747, Article 111747
• Main Authors: Xue, Xiaomin, Ye, Guanzhi, Zhang, Long, Zhu, Xiaolei, Liu, Qun, Rui, Gang, Geng, Guojun, Lin, Yihua, Chen, Xiaohui
• Format: Article
• Language: English
• Subjects: Cancer immunity; GNE-493; Immunogenic death; Lung cancer; PI3K
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2024.111747

[Display omitted] •PIK3CA reduced patient survival in lung cancer and negatively correlates with CD8 function.•PIK3 inhibitor GNE-493 inhibited the proliferation of lung cancer cells.•GNE-493 induced immunogenic death of lung cancer cells.•GNE-493 treatment enhanced the immune response by promoting IFN and other signaling pathways.•PIK3 inhibitor treatment promoted the activation and proliferation of CD8+ T cells. Phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer, playing pivotal roles in the pathophysiology of both malignant and immune cells. The impact of PI3K inhibitors on the tumor microenvironment (TME) within lung cancer remains largely unknown. In this study, we explored the regulatory effects of GNE-493, an innovative dual inhibitor of PI3K and mammalian target of rapamycin (mTOR), on the TME of lung cancer. First, through the analysis of The Cancer Genome Atlas-lung squamous cell carcinoma (LUSC) cohort, we found PIK3CA to be related to CD8 T cells, which may affect the overall survival rate of patients by affecting CD8 function. We herein demonstrated that GNE-493 can significantly inhibit tumor cell proliferation and promote cell apoptosis while increasing the expression of the immunogenic death-related molecules CRT and HSP70 using in vitro cell proliferation and apoptosis experiments on the murine KP lung cancer cell line and human A549 lung cancer cell line. Next, through the establishment of an orthotopic tumor model in vivo, it was found that after GNE-493 intervention, the infiltration of CD4+ and CD8+ T cells in mouse lung tumor was significantly increased, and the expression of CRT in tumors could be induced to increase. To explore the mechanisms underlying PI3K inhibition-induced changes in the TME, the gene expression differences of T cells in the control group versus GNE-493-treated KP tumors were analyzed by RNA-seq, and the main effector pathway of anti-tumor immunity was identified. The IFN/TNF family molecules were significantly upregulated after GNE-493 treatment. In summary, our findings indicate that GNE-493 promotes immunogenic cell death in lung cancer cells, and elucidates its regulatory impact on molecules associated with the adaptive immune response. Our study provides novel insights into how PI3K/mTOR inhibitors exert their activity by modulating the tumor–immune interaction.