CXCL17 Expression Predicts Poor Prognosis and Correlates with Adverse Immune Infiltration in Hepatocellular Carcinoma

Abstract

CXC ligand 17 (CXCL17) is a novel CXC chemokine whose clinical significance remains largely unknown. In the present study, we characterized the prognostic value of CXCL17 in patients with hepatocellular carcinoma (HCC) and evaluated the association of CXCL17 with immune infiltration. We examined CXCL17 expression in 227 HCC tissue specimens by immunohistochemical staining, and correlated CXCL17 expression patterns with clinicopathological features, prognosis, and immune infiltrate density (CD4 T cells, CD8 T cells, B cells, natural killer cells, neutrophils, macrophages). Kaplan-Meier survival analysis showed that both increased intratumoral CXCL17 (P = 0.015 for overall survival [OS], P = 0.003 for recurrence-free survival [RFS]) and peritumoral CXCL17 (P = 0.002 for OS, P<0.001 for RFS) were associated with shorter OS and RFS. Patients in the CXCL17low group had significantly lower 5-year recurrence rate compared with patients in the CXCL17high group (peritumoral: 53.1% vs. 77.7%, P<0.001, intratumoral: 58.6% vs. 73.0%, P = 0.001, respectively). Multivariate Cox proportional hazards analysis identified peritumoral CXCL17 as an independent prognostic factor for both OS (hazard ratio [HR] = 2.066, 95% confidence interval [CI] = 1.296–3.292, P = 0.002) and RFS (HR = 1.844, 95% CI = 1.218–2.793, P = 0.004). Moreover, CXCL17 expression was associated with more CD68 and less CD4 cell infiltration (both P<0.05). The combination of CXCL17 density and immune infiltration could be used to further classify patients into subsets with different prognosis for RFS. Our results provide the first evidence that tumor-infiltrating CXCL17+ cell density is an independent prognostic factor that predicts both OS and RFS in HCC. CXCL17 production correlated with adverse immune infiltration and might be an important target for anti-HCC therapies.

Cxcl17 -/- mice develop exacerbated disease in a T cell-dependent autoimmune model

“…Several groups have associated the expression of CXCL17 with tumor development, because tumor cells overexpressing CXCL17 induce bigger tumors and grow faster when implanted in mice . Several groups have reported that expression of Cxcl17 is up‐regulated in several cancers including esophageal, lung, breast, endometrium, liver, and pancreas, and CXCL17 expression correlates with poor survival and prognosis …”

CXCL17 Attenuates Imiquimod-Induced Psoriasis-like Skin Inflammation by Recruiting Myeloid-Derived Suppressor Cells and Regulatory T Cells

“…CXCL17 was reported to be highly expressed in epithelial cells and vascular endothelial cells (1). CXCL17 is also expressed in malignancy: in hepatocellular carcinoma, CXCL17 was produced mainly by tumor-infiltrating neutrophils and occasionally by the tumor cells (4). The receptor of CXCL17 was recently detected as GPR35/CXCR8, which is expressed in mucosal tissues, including the gastrointestinal tract and lung (5).…”

“…Several studies have proposed that CXCL17 might accelerate tumor progression (1,4,(6)(7)(8). CXCL17 was reported to be expressed in various types of tumor cells such as breast, lung, hepatic, and colon cancer (1,4,(6)(7)(8).…”

“…CXCL17 was reported to be expressed in various types of tumor cells such as breast, lung, hepatic, and colon cancer (1,4,(6)(7)(8). In hepatic carcinoma, CXCL17 expression is an independent indicator for poor prognosis (4). Moreover, CXCL17 was demonstrated to recruit myeloid-derived suppressor cells (MDSCs) to tumor sites and promote tumorigenesis through angiogenesis in a mouse model (7).…”

CD169 identifies an activated CD8+T cell subset in regional lymph nodes that predicts favorable prognosis in colorectal cancer patients

“…34 Briefly, the slides were loaded onto the Vectra slide scanner following the protocol. Representative areas for each LN were collected on 2-5 fields from each slide at a constant magnification of 200£.…”