Exploring the Immunomodulatory Potential of Pancreatic Cancer-Derived Extracellular Vesicles through Proteomic and Functional Analyses.

Autor: Piro, Anna, Cufaro, Maria Concetta, Lanuti, Paola, Brocco, Davide, De Lellis, Laura, Florio, Rosalba, Pilato, Serena, Pagotto, Sara, De Fabritiis, Simone, Vespa, Simone, Catitti, Giulia, Verginelli, Fabio, Simeone, Pasquale, Pieragostino, Damiana, Del Boccio, Piero, Fontana, Antonella, Grassadonia, Antonino, Di Ianni, Mauro, Cama, Alessandro, Veschi, Serena
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Zdroj: Cancers; May2024, Vol. 16 Issue 10, p1795, 18p
Abstrakt: Simple Summary: Pancreatic cancer (PC) develops resistance to current therapeutic approaches with a consequent dismal prognosis. Immunotherapy is an effective approach in several tumors, but PC is resistant to immunotherapy. Tumor-derived extracellular vesicles (EVs) may modulate immune responses by either dampening or inducing antitumor immune responses. In this study, we explored the immunomodulatory potential of pancreatic-cancer-derived extracellular vesicles through proteomic and functional approaches. Notably, proteins involved in the "Immune System" were highly enriched in the protein cargo of PC-derived EVs, which also included immunostimulatory proteins. Interestingly, the treatment of healthy donor-derived peripheral blood mononuclear cells (PBMCs) with EVs from one of the PC cell lines analyzed induced early activation markers in CD8+ and CD4+ lymphocytes. This was consistent with the proteomic and ELISA analyses. Our study indicates that even if PC is an immune-cold tumor, in some cases, PC-EVs may activate early immune responses. This finding might be relevant for the development of effective immunotherapeutic strategies in PC. Pancreatic cancer (PC) has a poor prognosis and displays resistance to immunotherapy. A better understanding of tumor-derived extracellular vesicle (EV) effects on immune responses might contribute to improved immunotherapy. EVs derived from Capan-2 and BxPC-3 PC cells isolated by ultracentrifugation were characterized by atomic force microscopy, Western blot (WB), nanoparticle tracking analysis, and label-free proteomics. Fresh PBMCs from healthy donors were treated with PC- or control-derived heterologous EVs, followed by flow cytometry analysis of CD8+ and CD4+ lymphocytes. The proteomics of lymphocytes sorted from EV-treated or untreated PBMCs was performed, and the IFN-γ concentration was measured by ELISA. Notably, most of the proteins identified in Capan-2 and BxPC-3 EVs by the proteomic analysis were connected in a single functional network (p = 1 × 10−16) and were involved in the "Immune System" (FDR: 1.10 × 10−24 and 3.69 × 10−19, respectively). Interestingly, the treatment of healthy donor-derived PBMCs with Capan-2 EVs but not with BxPC-3 EVs or heterologous control EVs induced early activation of CD8+ and CD4+ lymphocytes. The proteomics of lymphocytes sorted from EV-treated PBMCs was consistent with their activation by Capan-2 EVs, indicating IFN-γ among the major upstream regulators, as confirmed by ELISA. The proteomic and functional analyses indicate that PC-EVs have pleiotropic effects, and some may activate early immune responses, which might be relevant for the development of highly needed immunotherapeutic strategies in this immune-cold tumor. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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