1. Academic Validation
  2. M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance

M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance

  • Oncoimmunology. 2023 May 13;12(1):2210959. doi: 10.1080/2162402X.2023.2210959.
Naisheng Zheng 1 2 Tingting Wang 1 3 Qin Luo 1 4 Yi Liu 1 Junyao Yang 1 Yunlan Zhou 1 Guohua Xie 1 Yanhui Ma 1 Xiangliang Yuan 1 Lisong Shen 1
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Xinhua Hospital, , Shanghai Jiao Tong University School of MedicineShanghai, P.R. China.
  • 2 Institute of Molecular Medicine, Renji Hospital, , Shanghai Jiao Tong University School of MedicineShanghai, P.R. China.
  • 3 Department of Clinical Laboratory, The First Affiliated Hospital, , Zhejiang University School of MedicineHangzhou, Zhejiang, P.R. China.
  • 4 Department of Clinical Laboratory, Affiliated Dongguan People's Hospital, , Southern Medical UniversityDongguan, Guangdong, P.R. China.
Abstract

T-cell-based immune checkpoint blockade therapy (ICB) can be undermined by local immunosuppressive M2-like tumor-associated macrophages (TAMs). However, modulating macrophages has proved difficult as the molecular and functional features of M2-TAMs on tumor growth are still uncertain. Here we reported that immunosuppressive M2 macrophages render Cancer cells resistant to CD8+ T-cell-dependent tumor-killing refractory ICB efficacy by secreting exosomes. Proteomics and functional studies revealed that M2 macrophage-derived exosome (M2-exo) transmitted apolipoprotein E (ApoE) to Cancer cells conferring ICB resistance by downregulated MHC-I expression curbing tumor intrinsic immunogenicity. Mechanistically, M2 exosomal ApoE diminished the tumor-intrinsic ATPase activity of binding immunoglobulin protein (BiP) to decrease tumor MHC-I expression. Sensitizing ICB efficacy can be achieved by the administration of ApoE ligand, EZ-482, enhancing ATPase activity of BiP to boost tumor-intrinsic immunogenicity. Therefore, ApoE may serve as a predictor and a potential therapeutic target for ICB resistance in M2-TAMs-enriched Cancer patients. Collectively, our findings signify that the exosome-mediated transfer of functional ApoE from M2 macrophages to the tumor cells confers ICB resistance. Our findings also provide a preclinical rationale for treating M2-enriched tumors with ApoE ligand, EZ-482, to restore sensitivity to ICB immunotherapy.

Keywords

apolipoprotein E; exosomes; immune checkpoint blockade therapy; immunogenicity; macrophages.

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