A CD36-dependent non-canonical lipid metabolism program promotes immune escape and resistance to hypomethylating agent therapy in AML

  • Cell Rep Med. 2024 Jun 18;5(6):101592. doi: 10.1016/j.xcrm.2024.101592.
He-Zhou Guo  1 ,  Rui-Xue Feng  2 ,  Yan-Jie Zhang  3 ,  Ye-Hua Yu  3 ,  Wei Lu  3 ,  Jia-Jia Liu  3 ,  Shao-Xin Yang  3 ,  Chong Zhao  3 ,  Zhao-Li Zhang  3 ,  Shan-He Yu  2 ,  Hui Jin  4 ,  Si-Xuan Qian  4 ,  Jian-Yong Li  5 ,  Jiang Zhu  6 ,  Jun Shi  7
Affiliations
  • 1. Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China; Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao-Tong University, Shanghai, China.
  • 2. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao-Tong University, Shanghai, China.
  • 3. Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
  • 4. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
  • 5. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China. Electronic address: [email protected].
  • 6. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao-Tong University, Shanghai, China. Electronic address: [email protected].
  • 7. Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 38843841 DOI: 10.1016/j.xcrm.2024.101592
Abstract

Environmental lipids are essential for fueling tumor energetics, but whether these exogenous lipids transported into Cancer cells facilitate immune escape remains unclear. Here, we find that CD36, a transporter for exogenous lipids, promotes acute myeloid leukemia (AML) immune evasion. We show that, separately from its established role in lipid oxidation, CD36 on AML cells senses oxidized low-density lipoprotein (OxLDL) to prime the TLR4-LYN-MYD88-nuclear factor κB (NF-κB) pathway, and exogenous palmitate transfer via CD36 further potentiates this innate immune pathway by supporting ZDHHC6-mediated MyD88 palmitoylation. Subsequently, NF-κB drives the expression of immunosuppressive genes that inhibit anti-tumor T cell responses. Notably, high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling, leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression.

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