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The proteomics analysis of Chimeric exosomes

ABSTRACT: Immunotherapy is a breakthrough in the treatment of triple-negative breast cancer (TNBC), whereas is effective in a portion of patients. Our clinical studies found that lipid homeostasis imbalance and dendritic cells (DCs) dysfunction contributed to the immunosuppressive microenvironment in the lymph nodes (LNs) of TNBC patients following immunotherapy, which greatly affected the immunotherapeutic efficacy. Building on this, we introduce a chimeric exosomes-derived immunomodulator, EMV@SS-Toy, involving a polysulfide bond-bridged mesoporous silica nanoparticles (SS-MSN) as a reactive oxygen species (ROS) scavenger and responsive carrier nucleus, loading with the (IRE1α-XBP1) inhibitor toyocamycin (Toy) and coating with chimeric exosomes comprising DCs-derived exosomes and Salmonella outer membrane vesicles. This multifaceted immunomodulator can significantly enhance LNs’ homing via homologous targeting and chemokine-guided navigation, enabling a pathological ROS-responsive drug release, dual-stress pathway regulation, thereby restoring and DCs’ function and LNs’ immune microenvironment. As expected, the immunomodulator markedly boosted the responsiveness of TNBC to immunotherapy, exerting potent inhibition on both the primary tumor and metastases and establishing long-term immune surveillance. Our study provides potent directions for translational immunotherapy through optimizing the LNs’ microenvironment in TNBC.

ORGANISM(S): Mus <genus>

SUBMITTER: Qiuhua Luo

PROVIDER: PXD052986 | iProX | Mon Jun 10 00:00:00 BST 2024

REPOSITORIES: iProX

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Project description:As a type of secreted membrane vesicle, exosomes are emerging as an important mode of cell-to-cell communication. The objective of this study was to compare the abundance of transcripts present in the parental B16F0 cell to transcripts present in exosomes isolated from B16F0 conditioned media. Identifying local mechanisms of immunosuppression is a key barrier for expanding the clinical benefit of cancer immunotherapy. While exosomes are emerging as a new mode of intercellular communication, their role in establishing a malignant tissue niche remains unclear. Similar to the sculpting of tumor antigens during oncogenesis, a related hypothesis is that proteins secreted by malignant cells are shaped by somatic evolution. To test this hypothesis, we characterized the biological influence of tumor-derived exosomes on immune cell function. In particular, we analyzed exosomes from three melanoma models: B16F0, a non-immunogenic model of malignant melanoma; Cloudman S91, a model of immunogenic melanoma; and Melan-A, an immortalized melanocyte cell line. Using electron microscopy, exosomes derived from all three cell lines were morphologically similar. The exosomes contained receptors derived from the parent cell as demonstrated by IL12RB2 expression on B16F0 exosomes and intact mRNAs. Furthermore, transcript profiling of B16F0 exosomes and cells suggested that exosomal mRNA is enriched for mRNAs that target immune-related pathways, including Ptpn11 that inhibited T cell proliferation and Dnmt3a that inhibited T cell production of IFN-gamma. Functionally, B16F0 exosomes dose-dependently suppressed cell proliferation and the expression of IL12RB2 in primary CD8+ T cells. In contrast, Cloudman S91 exosomes promoted T cell proliferation and Melan-A exosomes had a negligible effect on primary CD8+ T cells. Collectively, the results are consistent with somatic editing of exosomal payloads and suggest that exosomes establish a density-dependent field effect by altering the activity of immune cells that enter the tumor microenvironment.

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The proteomics analysis of Chimeric exosomes

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