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

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

Disclosure statement

No potential conflict of interest was reported by the authors.

Data and materials availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2210959.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (No. 81772525, 81672363, 81402148, and 81472244).