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

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

  • J Immunother Cancer. 2021 Aug;9(8):e003093. doi: 10.1136/jitc-2021-003093.
Pu Sun  # 1 2 Xi Zhang  # 1 Rong-Jing Wang  # 2 3 Qing-Yang Ma 3 Lan Xu 1 Yi Wang 1 Hui-Ping Liao 3 Hai-Long Wang 3 Lan-Dian Hu 3 Xiangyin Kong 4 3 Jian Ding 4 5 Ling-Hua Meng 6 2
Affiliations

Affiliations

  • 1 Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • 4 University of Chinese Academy of Sciences, Beijing, China xykong@sibs.ac.cn jding@simm.ac.cn lhmeng@simm.ac.cn.
  • 5 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 6 Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China xykong@sibs.ac.cn jding@simm.ac.cn lhmeng@simm.ac.cn.
  • # Contributed equally.
Abstract

Background: The 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.

Methods: The 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.

Results: CYH33 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.

Conclusions: CYH33 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.

Keywords

immunologic memory; immunomodulation; lymphocytes; macrophages; tumor microenvironment; tumor-infiltrating.

Figures
Products