CCR9

Detailed Information

CC chemokine receptor 9 (CCR9) is a member of the chemokine receptor family and belongs to the group of G protein-coupled receptors with seven transmembrane domains. The chemokine receptor family comprises important cell-surface receptors that, upon binding with chemokines, regulate various cellular processes, including migration, differentiation, and proliferation. These receptors are classified into four subfamilies: CC, CXC, CX3C, and C. CCR9 is part of the CC subfamily.

CCR9 has two transcript variants: transcript A (369 amino acids, ~42 kDa) and transcript B (357 amino acids, ~40.8 kDa). Due to its structural and sequence similarity to CCR6 and CCR7, it was reclassified as CCR9. Its physiological functions are largely mediated by the seven transmembrane domains spanning amino acids 65–317.

Expression and Functions of CCR9

CCR9 is primarily expressed in immature thymocytes, peripheral CD8+ T cells, certain dendritic cells, and small intestinal epithelial cells, where it contributes to maintaining immune homeostasis. The receptor interacts with its ligand CCL25 to mediate thymocyte migration during development and direct the homing of gut-associated immune cells.

Research indicates that CCR9 plays an important role in multiple diseases, including inflammatory bowel disease, acute hepatitis, and rheumatoid arthritis. In addition, elevated expression of CCR9 has been observed in several malignancies, where it is often associated with drug resistance, metastasis, and poor prognosis. This suggests CCR9 is involved in biological processes relevant to cancer progression, including colorectal cancer, melanoma, prostate cancer, and non-small cell lung cancer.

The Ligand of CCR9

The specific ligand for CCR9 is thymus-expressed chemokine (TECK), also known as CCL25. CCL25 is encoded on chromosome 19p13.2 and belongs to the CC chemokine family. It consists of 150 amino acids, including a 23-amino-acid signal peptide at the N-terminus. CCL25 is predominantly expressed in the thymus and small intestinal epithelial cells, but low expression is also observed in the testis, brain, liver, and activated pro-T cells.

Figure 1. CCR9 promotes tumor chemoresistance through the CCL25/CCR9 signaling axis, activating PI3K-AKT and JAK-STAT pathways, and via P-gp/ERM/F-actin interactions. (Tu Z, et al., 2016)

CCR9 and CCL25 together form a regulatory axis that is increasingly studied in cancer biology. Evidence suggests that serum CCL25 is highly correlated with MMP-9, VEGF-D, and AKT, pointing to a role of the CCR9/CCL25 axis in PI3K/AKT pathway activation and downstream effector expression. Moreover, apoptosis of MOLT4 cells induced by cycloheximide can be suppressed by CCR9/CCL25 signaling. Binding of CCL25 to CCR9 activates PI3K, leading to AKT phosphorylation, which in turn activates multiple survival-related molecules such as Bad and GSK-3β, thereby promoting cell survival. These findings suggest that CCR9 and its ligand CCL25 may represent potential molecular targets in cancer research.

CCR9/CCL25-Mediated Signaling Pathways in Cancer

PI3K/AKT Pathway

The PI3K/AKT pathway is a major intracellular signaling cascade known to be associated with tumorigenesis and malignant progression. It is negatively regulated by tumor-related genes such as PTEN, CTMP, and SHLP2. Recent studies have shown that CCR9/CCL25 can activate PI3K/AKT signaling, contributing to anti-apoptotic processes in non-small cell lung cancer cells and prostate cancer cells, including resistance to etoposide-induced apoptosis. Similar anti-apoptotic effects have been reported in breast and ovarian cancer models, indicating CCR9/CCL25 may regulate tumor cell apoptosis via the PI3K/AKT pathway.

JAK/STAT Pathway

The JAK/STAT pathway is a rapid and efficient signaling route from the cell surface to the nucleus. Activation of STAT3 in particular plays a critical role in cell growth, proliferation, and transformation. Studies indicate that CCR9 signaling can attenuate cytotoxic immune responses through the JAK/STAT pathway, and suppression of CCR9 expression may enhance tumor-specific T cell-mediated immunotherapy. This highlights the potential significance of studying CCR9/CCL25 interactions in tumor immunology.

Roles of CCR9 in Cancer

Chemokines and their receptors participate in nearly all stages of cancer progression, including lymphocyte recruitment, angiogenesis, proliferation, survival, invasion, and metastasis. CCR9 and CCL25 are expressed at high levels in multiple cancers, where they contribute to invasion, migration, resistance to apoptosis, and treatment resistance. Below are examples of specific cancer-related findings:

• T-cell Leukemia: CCR9 is highly expressed in CD4+ T cells from acute and chronic T-cell leukemia but absent in normal CD4+ T cells. CCR9/CCL25 interactions regulate apoptotic signaling, proliferation, and survival through pathways involving FKHR, GSK-3β, and possibly Notch1 and Livin.
• Colorectal Cancer: CCR9 is highly expressed in adenomas and pre-invasive colorectal carcinoma, and the CCR9/CCL25 axis significantly enhances invasive potential in vitro.
• Prostate Cancer: CCR9 expression correlates with lymph node metastasis. CCR9/CCL25 interactions reduce chemotherapy-induced apoptosis, while blocking the axis restores apoptosis and reduces invasiveness.
• Ovarian Cancer: CCR9 and CCL25 are highly expressed in epithelial ovarian cancer and correlate with lymph node metastasis, histological grade, and clinical stage. Functional assays confirm CCR9/CCL25 promotes invasion and migration.
• Breast Cancer: CCR9 is overexpressed in tumors compared with adjacent tissues, especially in poorly differentiated tumors. CCR9/CCL25 promotes cisplatin resistance through PI3K/AKT signaling and enhances invasiveness.
• Pancreatic Cancer: CCR9/CCL25 promotes proliferation and invasion. Expression levels are highest in draining lymph nodes, correlating with disease stage and differentiation.
• Lung Adenocarcinoma: CCR9 expression correlates positively with ALDH1A1 and poor prognosis, enhancing cancer stem cell migration and invasion.
• Non-Small Cell Lung Cancer: CCR9 is overexpressed in tumor tissues and cell lines but absent in normal bronchial epithelial cells, and it promotes invasion and migration.
• Hepatocellular Carcinoma: CCR9 expression is elevated and associated with poor prognosis, possibly through modulation of cell cycle regulators (p21, p27, cyclin D1).
• Melanoma: CCR9 is specifically expressed in intestinal metastases of melanoma but not in metastases to other organs. CCR9/CCL25 enhances migration and invasion, effects that can be reduced by CCR9 blockade.

CCR9-Targeted Drug Research

Several experimental drugs targeting CCR9 have been developed, including SRB1, NR11/1943 (Norgine), OB-003, CCX-025, MLN-3126, Vercirnon Sodium, and CCX-5072. These agents function as CCR9 antagonists by blocking its interaction with CCL25, thereby inhibiting CCR9-mediated T cell migration and activation. Indications under investigation include inflammatory bowel disease, cancer, and other immune-, gastrointestinal-, and mucosal-related conditions.

Most candidates are small molecules, with one antibody among them, and they are at different stages of research, ranging from preclinical studies to clinical trials. Institutions involved include Sunrock Biopharma SL, Norgine Ltd., and Orion Biotechnology Canada Ltd.

Given the growing evidence that chemokines and their receptors are central to tumor biology, CCR9 is increasingly considered both a potential prognostic biomarker and a target for therapeutic strategies. Further research is needed to provide a pharmacological basis for CCR9-targeted interventions.