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.

Chrysin Inhibits TAMs-Mediated Autophagy Activation via CDK1/ULK1 Pathway and Reverses TAMs-Mediated Growth-Promoting Effects in Non-Small Cell Lung Cancer

“…TAMs can secrete various cytokines and chemokines, such as epidermal growth factor (EGF), transforming growth factor (TGF), and IL-10 (interleukin-10), which can directly stimulate tumor cell proliferation and facilitate tumor cell migration and invasion, thereby driving tumor growth and dissemination [ 27 , 28 ]. Furthermore, TAMs are among the principal innate immune cell populations in tumors, with M2-TAMs capable of suppressing immune surveillance, aiding tumor cell immune evasion, protecting tumors from cytotoxic immune reactions, and promoting tumor progression [ 29 ]. Additionally, TAMs influence tumor growth by modulating the autophagic process of tumor cells.…”

Role of Exosomes in Cancer and Aptamer-Modified Exosomes as a Promising Platform for Cancer Targeted Therapy

“…While tumor-intrinsic YTHDF1, a versatile and powerful m6A reader, was demonstrated to drive immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation, an exosome-mediated CRISPR/Cas9 system was shown to introduce YTHDF1 deficiency and restore expression of MHC-I and tumor immune surveillance [ 230 ]. Additionally, M2 macrophage-derived exosome was revealed to confer cancer cell resistance to ICT via apolipoprotein E (ApoE)-mediated downregulation of MHC-I [ 231 ]. Upregulated expression of PD-L1 on surface of tumor cells is a common strategy hijacked by various type of cancer to evade immune surveillance [ 232 ].…”

“…Just as almost all treatments of cancer except for surgery, the accompanying resistance to tumor immunotherapy is an inevitable obstacle to be overcome currently [ 390 , 391 ]. As aforementioned above, many exosomes-based mechanisms underlying evasion of immune surveillance confer to resistance to immunotherapy including ICT [ 206 , 230 , 231 ], and CAR-T therapy in cancer as well [ 247 ]. In addition, reshaped TME resulted from conventional treatment such as radiotherapy, as well as ICT has also been increasingly recognized as key player in development of acquired resistance to cancer immunotherapy [ 392 , 393 ], which adding new dimension to the field of even complicated exosome-mediated mechanisms [ 394 ].…”

Haematopoietic cell‐derived exosomes in cancer development and therapeutics: From basic science to clinical practice

“…Zheng et al. showed that exosomal ApoE from M2‐Exos suppressed the ATPase activity of BiP, resulting in decreased MHC‐I expression, thereby resisting ICBT therapy 91 . Cianciaruso et al.…”

“…90 Zheng et al showed that exosomal ApoE from M2-Exos suppressed the ATPase activity of BiP, resulting in decreased MHC-I expression, thereby resisting ICBT therapy. 91 Cianciaruso et al showed that tumour-associated macrophagederived exosomes (TAM-Exos) and cancer cell-derived exosomes were the main cellular sources of exosomes in a syngeneic MC38 colon cancer model. TAM-Exos isolated with an anti-CSF1R exhibited an M1-like tumourassociated macrophage (TAM) signature and promoted T-cell proliferation even though the TAM cells themselves exhibited an M2-like phenotype.…”