Chemokine Receptor-Targeted Therapies: Special Case for CCR8

SIMPLE SUMMARY: Antibodies directed at so-called immune checkpoint molecules represent a substantial improvement in cancer therapy. These biological reagents highlight the exquisite interplay between cancer and our own immune system. Cancer progression is enabled by establishing a compartment of suppressive immune cells within the tumor. Therefore, elimination of these suppressor cells is an attractive strategy to augment beneficial anti-tumor immunity and to further improve the newly established immune checkpoint therapy. This review focuses on CCR8, a chemokine receptor highly expressed on suppressive immune cells, and its potential value as a novel target in cancer therapy. ABSTRACT: Immune checkpoint blockade inhibitors (CBIs) targeting cytotoxic T lymphocyte associated protein-4 (CTLA-4) and program death receptor-1 (PD-1) or its ligand-1 (PD-L1) have transformed the outlook of many patients with cancer. This remarkable progress has highlighted, from the translational point of view, the importance of immune cells in the control of tumor progression. There is still room for improvement, since current CBI therapies benefit a minority of patients. Moreover, interference with immune checkpoint receptors frequently causes immune related adverse events (irAEs) with life-threatening consequences in some of the patients. Immunosuppressive cells in the tumor microenvironment (TME), including intratumoral regulatory T (Treg) cells, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), contribute to tumor progression and correlate with a negative disease outlook. Recent reports revealed the selective expression of the chemokine receptor CCR8 on tumor Treg cells, making CCR8 a promising target in translational research. In this review, I summarize our current knowledge about the cellular distribution and function of CCR8 in physiological and pathophysiological processes. The discussion includes an assessment of how the removal of CCR8-expressing cells might affect both anti-tumor immunity as well as immune homeostasis at remote sites. Based on these considerations, CCR8 appears to be a promising novel target to be considered in future translational research.