CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase.

Abstract

BACKGROUND AND AIMS:

We previously demonstrated that cancer-associated fibroblasts (CAFs) promote tumor growth through recruitment of myeloid-derived suppressor cells (MDSCs). 5-lipoxygenase (5-LO) is highly expressed in myeloid cells and is critical for synthesizing leukotriene B4 (LTB4), which is involved in tumor progression by activating its receptor leukotriene B4 receptor type 2 (BLT2). In this study, we investigated whether and how CAFs regulate MDSC function to enhance cancer stemness, the driving force of the cancer aggressiveness and chemotherapy refractoriness, in highly desmoplastic intrahepatic cholangiocarcinoma (ICC).

APPROACH AND RESULTS:

RNA-sequencing analysis revealed enriched metabolic pathways but decreased inflammatory pathways in cancer MDSCs compared with blood MDSCs from patients with ICC. Co-injection of ICC patient-derived CAFs promoted cancer stemness in an orthotopic ICC model, which was blunted by MDSC depletion. Conditioned media (CM) from CAF-educated MDSCs drastically promoted tumorsphere formation efficiency and stemness marker gene expression in ICC cells. CAF-CM stimulation increased expression and activity of 5-LO in MDSCs, while 5-LO inhibitor impaired the stemness-enhancing capacity of MDSCs in vitro and in vivo. Furthermore, IL-6 and IL-33 primarily expressed by CAFs mediated hyperactivated 5-LO metabolism in MDSCs. We identified the LTB4-BLT2 axis as the critical downstream metabolite signaling of 5-LO in promoting cancer stemness, as treatment with LTB4 was elevated in CAF-educated MDSCs, or blockade of BLT2 (which was preferentially expressed in stem-like ICC cells) significantly reduced stemness-enhancing effects of CAF-educated MDSCs. Finally, BLT2 blockade augmented chemotherapeutic efficacy in ICC patient-derived xenograft models.

CONCLUSIONS:

Our study reveals a role for CAFs in orchestrating the optimal cancer stemness-enhancing microenvironment by educating MDSCs, and suggests the 5-LO/LTB4-BLT2 axis as promising therapeutic targets for ICC chemoresistance by targeting cancer stemness.

• Authors: Yuli Lin, Qian Cai, Yu Chen, Tiancong Shi, Weiren Liu, Li Mao, Bo Deng, Zhen Ying, Yuan Gao, Haoyang Luo, Xuguang Yang, Xiaowu Huang, Yinghong Shi, Rui He
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 75 Issue 1 Pg. 28-42 (01 2022) ISSN: 1527-3350 [Electronic] United States
• PMID: 34387870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by the American Association for the Study of Liver Diseases.

Chemical References

• Culture Media, Conditioned
• LTB4R2 protein, human
• Lipoxygenase Inhibitors
• Receptors, Leukotriene B4
• Arachidonate 5-Lipoxygenase
• ALOX5 protein, human

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Arachidonate 5-Lipoxygenase (metabolism)
• Bile Duct Neoplasms (drug therapy, pathology)
• Bile Ducts, Intrahepatic (pathology)
• Cancer-Associated Fibroblasts (metabolism)
• Cell Communication
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cholangiocarcinoma (drug therapy, pathology)
• Culture Media, Conditioned (metabolism)
• Drug Resistance, Neoplasm
• Humans
• Lipoxygenase Inhibitors (pharmacology)
• Male
• Mice
• Myeloid-Derived Suppressor Cells (metabolism)
• Neoplastic Stem Cells (drug effects, pathology)
• Receptors, Leukotriene B4 (antagonists & inhibitors, metabolism)
• Tumor Microenvironment (drug effects)
• Xenograft Model Antitumor Assays