PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8⁺T cells and promoting fatty acid metabolism

Abstract

BackgroundThe phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer and plays important roles in both malignant and immune cells. The effect of PI3Kα inhibitors on the tumor microenvironment (TME) remains largely unknown. Here, we investigated the modulation of the TME by a clinical PI3Kα-specific inhibitor CYH33.MethodsThe activity of CYH33 against a panel of murine tumors in the immune-competent context or athymic mice was detected. Single-cell RNA sequencing and multi-parameter flow cytometry were performed to determine the immune profiling of TME. The effect of CYH33 on immune cells was conducted with primary murine cells.ResultsCYH33 exhibited more potent antitumor activity in immune-competent context. CYH33 enhanced the infiltration and activation of CD8+T and CD4+T cells, while attenuating M2-like macrophages and regulatory CD4+T cells. Increase in memory T cells was confirmed by the induction of long-term immune memory on CYH33 treatment. Mechanistically, CYH33 relieved the suppressed expansion of CD8+T cells via preferential polarization of the macrophages to the M1 phenotype. CYH33 promoted fatty acid (FA) metabolism in the TME, while FA enhanced the activity of CD8+T cells in vitro. The combination of CYH33 with the FA synthase (FASN) inhibitor C75 synergistically inhibited tumor growth with enhanced host immunity.ConclusionsCYH33 induces immune activation and synergizes with FASN inhibitor to further promote the antitumor immunity, which gains novel insights into how PI3K inhibitors exert their activity by modulating TME and provides a rationale for the concurrent targeting of PI3K and FASN in breast cancer treatment.

Landscape of the oncogenic role of fatty acid synthase in human tumors

“…A statistically significant difference was found between FASN and CD8 + T-cells in HNSC, KIRC, OV, and BRCA ( Figure 16 ). These results were consistent with those of published studies, which revealed that phosphatidylinositol 3-kinase α inhibitor could promote fatty acid metabolism to activate CD8+T cells, and a combination of the inhibitor and FASN inhibitor could enhance immunity to decrease breast tumor growth [ 44 ]. A favorable relationship was also found between FASN expression and cancer-associated fibroblasts in CESC, KIRC, KIRP, OV, and UVM.…”

EPHX2 Inhibits Colon Cancer Progression by Promoting Fatty Acid Degradation

“…Hypoxia is an internal environment in almost all solid tumors. Hypoxia interacts with fatty acid metabolism and can regulate tumor immunity ( 17 , 18 ). Therefore, the differences in the immune cell content and hypoxia signal pathway between the cluster1 and cluster2 groups were evaluated.…”

Managing the TME to improve the efficacy of cancer therapy

“…Reports using select PI3K inhibitors suggest potential use toward achieving similar results. Sun et al report on the compound CYH33 (an inhibitor of the PI3K alpha isoform) (43). CYH33 exhibited a potent antitumor activity in an immune-competent context by enhancing the infiltration and activation of CD8+T and CD4+T cells, while attenuating M2like macrophages and regulatory CD4+T cells.…”