Abstract
BackgroundRecent data indicated that macrophages may mutually interact with cancer cells to promote tumor progression and chemoresistance, but the interaction in cholangiocarcinoma (CCA) is obscure.Methods10x Genomics single-cell sequencing technology was used to identified the role of macrophages in CCA. Then, we measured the expression and prognostic role of macrophage markers and aPKCɩ in 70 human CCA tissues. Moreover, we constructed monocyte-derived macrophages (MDMs) generated from peripheral blood monocytes (PBMCs) and polarized them into M1/M2 macrophages. A co-culture assay of the human CCA cell lines (TFK-1, EGI-1) and differentiated PBMCs-macrophages was established, and functional studies in vitro and in vivo was performed to explore the interaction between cancer cells and M2 macrophages. Furthermore, we established the cationic liposome-mediated co-delivery of gemcitabine and aPKCɩ-siRNA and detect the antitumor effects in CCA.ResultsM2 macrophage showed tumor-promoting properties in CCA. High levels of aPKCɩ expression and M2 macrophage infiltration were associated with metastasis and poor prognosis in CCA patients. Moreover, CCA patients with low M2 macrophages infiltration or low aPKCɩ expression benefited from postoperative gemcitabine-based chemotherapy. Further studies showed that M2 macrophages-derived TGFβ1 induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance in CCA cells through aPKCɩ-mediated NF-κB signaling pathway. Reciprocally, CCL5 was secreted more by CCA cells undergoing aPKCɩ-induced EMT and consequently modulated macrophage recruitment and polarization. Furthermore, the cationic liposome-mediated co-delivery of GEM and aPKCɩ-siRNA significantly inhibited macrophages infiltration and CCA progression.Conclusionour study demonstrates the role of Macrophages-aPKCɩ-CCL5 Feedback Loop in CCA, and proposes a novel therapeutic strategy of aPKCɩ-siRNA and GEM co-delivered by liposomes for CCA.
Highlights
Recent data indicated that macrophages may mutually interact with cancer cells to promote tumor progression and chemoresistance, but the interaction in cholangiocarcinoma (CCA) is obscure
High levels of Atypical protein kinase C iota (aPKCɩ) expression and M2 macrophage infiltration were associated with metastasis and poor prognosis in CCA patients
Further studies showed that M2 macrophages-derived TGFβ1 induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance in CCA cells through aPKCɩ-mediated NF-κB signaling pathway
Summary
Recent data indicated that macrophages may mutually interact with cancer cells to promote tumor progression and chemoresistance, but the interaction in cholangiocarcinoma (CCA) is obscure. Cholangiocarcinoma (CCA) is one of the most highly malignant and lethal cancers with limited overall survival and is notorious for its rapid progression, early metastasis and therapeutic resistance. The tumor microenvironment (TME) plays a significant role in promoting cancer progression, invasion, metastasis and chemoresistance [5]. TAMs often display an alternatively activated (M2) phenotype and enhance tumor malignancy in the majority of cases [6], and cancer cells can actively modulate the recruitment and activation of macrophages to enhance tumor growth and metastasis [7, 8]. Kitano et al [11] identified a risk signature, derived from the integration of intratumoral neutrophils, macrophages, C
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