Tumor-derived exosomal CCT6A serves as a matchmaker introducing chemokines to tumor-associated macrophages in pancreatic ductal adenocarcinoma

Tumor-derived exosomal CCT6A serves as a matchmaker introducing chemokines to tumor-associated macrophages in pancreatic ductal adenocarcinoma

Abstract M2-polarized tumor-associated macrophages (TAMs) are a key factor contributing to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). While various factors within the tumor microenvironment (TME) drive their formation, the role of PDAC-derived exosomes in this process remains unc...

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Main Authors: Tianyin Ma, Wing-Wa Guo, Minghe Zhang, Wenzhi He, Cairang Dongzhi, Xiangdong Gongye, Peng Xia, Yibo Chai, Zhang Chen, Yimin Zhu, Chengming Qu, Jie Liu, Zhiyong Yang, Weijie Ma, Ming Tian, Yufeng Yuan
Format: Article
Language:English
Published: Nature Publishing Group 2025-05-01
Series:Cell Death and Disease
Online Access:https://doi.org/10.1038/s41419-025-07720-y
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Summary:Abstract M2-polarized tumor-associated macrophages (TAMs) are a key factor contributing to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). While various factors within the tumor microenvironment (TME) drive their formation, the role of PDAC-derived exosomes in this process remains unclear. We aim to clarify the regulatory impacts of tumor-derived exosomes to TAMs. After the intratumoral injection to subcutaneous tumor of C57BL/6 mice, we demonstrated PDAC-derived exosomes exacerbate PDAC progression, accompanied with upregulated M2 phenotype of TAMs and unaffected proliferation signatures. Through intratumoral injection model and multi-Omics analyses, we identified CCT6A as a novel tumor-derived exosomal protein, bridging TAMs M2 polarization and PDAC prognosis. Co-culture with exosomes derived from CCT6Ahigh PDAC leads to greater M2 phenotype of TAMs via PI3K-AKT signaling. According to proteomics data, chemokines’ abundance reduces over tenfold once exosomal CCT6A absence, including CXCL1, CXCL3, CCL20 and CCL5, whose interaction with CCT6A in PDAC cells was confirmed by interactomics data. Moreover, we found silencing CCT6A abrogated the antagonism effects of CD47 antibody immunotherapy. Our findings implied that the subunit of the T-complex protein Ring Complex (TRiC) CCT6A serves as a matchmaker during exosome-mediated chemokines transfer from PDAC to TAMs. Silencing CCT6A effectively sensitized PDAC to CD47 antibody immunotherapy in vivo.
ISSN:2041-4889

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