CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma

Abstract

Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within tumor microenvironment. However, the tropism regulation and functions of these cells in HCC are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1 cells toward HCC invasive margin, approximately 80% of which were CD14 monocytes. Clinically, high-density of marginal CCR1 CD14 monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor-educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro-tumor factors and activating STAT1/3, ERK1/2 and AKT signaling in HCC cells. Meanwhile, tumor-derived CCR1 CD14 monocytes expressed significantly higher levels of PD-L1, B7-H3, and TIM-3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor-infiltrating CCR1 CD14 monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (IDO and ARG), inflammatory/pro-angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15-CCR1 axis forested an inflammatory microenvironment enriched with CCR1 monocytes and led to increased metastatic potential of HCC cells CONCLUSION: A complex tumor-promoting inflammatory microenvironment was shaped by CCL15-CCR1 axis in human HCC. Blockade of CCL15-CCR1 axis in HCC could be an effective anti-cancer therapy. This article is protected by copyright. All rights reserved.

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

“…Above finding prompted us to explore the potential mechanism(s) of PD‐L1 upregulation by CAFs. Prior literature suggests that PD‐L1 upregulated by some cytokines in tumor microenvironment, such as CCL15, IFN‐γ . To determined which cytokines expressed in CAFs were different from normal fibroblasts, qRT‐PCR was performed to scrutinize an amount of six CAFs cells.…”

“…Hence, we speculated that CXCL5 may play a significant role in PD‐L1 expression in melanoma and CRC cells. Notably, other researches showed that serum CXCL5 concentration was significantly higher in nonsmall cell lung cancer patients than those in healthy controls . Those analyses have demonstrated that CXCL5 as a potential biomarker for cancers.…”

“…Prior literature suggests that PD-L1 upregulated by some cytokines in tumor microenvironment, such as CCL15, IFN-γ. 12,16 To determined which cytokines expressed in CAFs were different from normal fibroblasts, qRT-PCR was performed to scrutinize an amount of six CAFs cells. CXCL5, CXCL2, MMP3, and so on, were overexpressed cytokines in CAFs with the reference to normal fibroblasts cell lines 3T3 (Fig.…”

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