M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance
Naisheng Zheng, Tingting Wang, Qin Luo, Yi Liu, Junyao Yang, Yunlan Zhou, Guohua Xie, Yanhui Ma, Xiangliang Yuan, Lisong Shen
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.