CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

Abstract

CC chemokines (or β-chemokines) are 28 chemotactic cytokines with an N-terminal CC domain that play an important role in immune system cells, such as CD4+ and CD8+ lymphocytes, dendritic cells, eosinophils, macrophages, monocytes, and NK cells, as well in neoplasia. In this review, we discuss human CC motif chemokine ligands: CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 (CC motif chemokine receptor CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 ligands). We present their functioning in human physiology and in neoplasia, including their role in the proliferation, apoptosis resistance, drug resistance, migration, and invasion of cancer cells. We discuss the significance of chemokine receptors in organ-specific metastasis, as well as the influence of each chemokine on the recruitment of various cells to the tumor niche, such as cancer-associated fibroblasts (CAF), Kupffer cells, myeloid-derived suppressor cells (MDSC), osteoclasts, tumor-associated macrophages (TAM), tumor-infiltrating lymphocytes (TIL), and regulatory T cells (Treg). Finally, we show how the effect of the chemokines on vascular endothelial cells and lymphatic endothelial cells leads to angiogenesis and lymphangiogenesis.

CC Chemokine Receptors in Lung Adenocarcinoma: The Inflammation-Related Prognostic Biomarkers and Immunotherapeutic Targets

“… 69 , 70 Furthermore, CC chemokine receptors, activated by binding to cytokines of the CC chemokine family, are closely associated with immune and inflammation response. 51 , 71 , 72 And the chemokine system plays a key role in the initiation of naive T cells, cell fate determination such as effector and memory cell differentiation, and regulatory T cell functions, and could position cells for host defense and immunity. 71 Recent studies in vivo and in vitro also demonstrated important roles for CC chemokine receptors in cancer processes.…”

“… 73–76 And CCR10, activated by CCL27 and CCL28, showed an effect on tumor vascularization by recruiting anti-cancer tumor-infiltrating lymphocytes (TILs) and regulatory T cells (Tregs). 72 …”

Genetic variation analyses indicate conserved SARS‐CoV‐2–host interaction and varied genetic adaptation in immune response factors in modern human evolution

“…CCR9 and its specific ligand CCL25 are categorized as a mucosal chemokine system, which is responsible for recruiting a subset of T cells to the lamina propria of the small intestine (Kunkel et al, 2000;Norment et al, 2000;Vicari et al, 1997;Zlotnik & Yoshie, 2012). The axis of CCL-25-CCR9 has been investigated as a therapeutic target of Crohn's disease, tumors, and autoimmunity (Biswas et al, 2019;Korbecki et al, 2020;Pathak & Lal, 2020;Xu et al, 2020). CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways throughout the sustained immune response to airway pathogens such as influenza viruses (Wein et al, 2019).…”

Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?

“…Finally, in a murine model of PDAC, the disruption of CCR5/CCL5 signaling, either by reducing CCL5 production by tumor cells (shRNA) or by systemic administration of the CCR5 inhibitor TAK-779, results in decreased Treg recruitment to the tumor and smaller tumors [ 110 ] that led the authors to suggest the potential use of such an inhibitor in clinic to inhibit Treg recruitment. However, as CCL5 could also favor the recruitment of antitumor effectors such as NK cells, Th1 CD4 + T cells and cytotoxic CD8 + T lymphocytes (for review, [ 111 ]), its blockade will be deleterious, except if combined in a bispecific format with a specific TA-Treg marker.…”