A positive feedback loop sustained by macrophages, the atypical protein kinase C iota (aPKCι), and the C-C motif chemokine 5 (CCL5) in the tumor microenvironment may accelerate the progression of cholangiocarcinoma (CCA), according to results of a new study published in the Journal of Experimental & Clinical Cancer Research.

The researchers also showed that patients with high aPKCι expression did not respond to postoperative chemotherapy, in contrast to those with low aPKCι expression, who responded well.

“These findings indicate that aPKCι and M2 macrophage infiltration are associated with chemoresistance in CCA,” the authors wrote. Mechanistically, they showed that tumor-associated macrophages (TAMs) induced gemcitabine resistance by inhibiting apoptosis.

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They demonstrated that aPKCɩ/p62 guided the activation of the nuclear factor-κB pathway in CCA. Moreover, the transforming growth factor β1 expressed by TAMs induced epithelial-mesenchymal transition (EMT) in CCA cells. In turn, CCA cells undergoing aPKCɩ-induced EMT secreted more CCL5, thereby modulating macrophage recruitment and polarization.

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CCA tissues showed a higher amount of M2 macrophages, which expressed higher levels of tumor-promoting molecules, and a lower amount of M1 macrophages than pair-matched paratumor tissues. Subsequent analyses of the molecular content suggested that M2 macrophages (aPKCι and CD [cluster of differentiation] 206+), but not M1 macrophages (CD80+), may contribute to the progression and dismal prognosis of CCA.

CCA tissues were enriched in aPKCι, CD68, and CD206 when compared to paratumor tissues. Overexpression of aPKCι and CD206 was associated with lymph node metastasis, tumor-node-metastasis (TNM) stage 3-4, and moderate/poor differentiation.

Overexpression of CD68 was also associated with lymph node metastasis and TNM stage 3-4. In contrast, CD80 showed no association with any of the clinicopathological features analyzed.

Accordingly, patients with high levels of aPKCι, CD68, or CD206, but not CD80, had worse overall survival (OS). Further analyses suggested aPKCι and CD206 as independent prognostic factors for OS in patients with CCA.


Yang T, Deng Z, Xu L, et al. Macrophages-aPKCɩ-CCL5 feedback loop modulates the progression and chemoresistance in cholangiocarcinoma. J Exp Clin Cancer Res. 2022;41(1):23. doi:10.1186/s13046-021-02235-8