Chemokine Pathways in Cutaneous Melanoma: Their Modulation by Cancer and Exploitation by the Clinician

SIMPLE SUMMARY: Despite significant advances in immunotherapy seen in the last decade, melanoma accounts for 2500 deaths a year in the UK. There remains an unmet clinical need to improve melanoma treatment. Melanoma is known as the “archetypal immunogenic tumour”, with a dense immune infiltrate. Chemokines are chemoattractant cytokines, essential for the positioning of all immune cells. This review outlines how the interplay of chemokine networks can enable melanoma tumours to survive, grow, metastasise, and evade anticancer immune responses. By better understanding how melanomas can exploit chemokine pathways, new targets to therapy may be revealed. ABSTRACT: The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; however, limitations to treatment still exist. Cutaneous melanoma lesions feature a dense cell infiltrate, coordinated by chemokines, which control the positioning of all immune cells. Melanomas are able to use chemokine pathways to preferentially recruit cells, which aid their growth, survival, invasion and metastasis, and which enhance their ability to evade anticancer immune responses. Aside from this, chemokine signalling can directly influence angiogenesis, invasion, lymph node, and distal metastases, including epithelial to mesenchymal transition-like processes and transendothelial migration. Understanding the interplay of chemokines, cancer cells, and immune cells may uncover future avenues for melanoma therapy, namely: identifying biomarkers for patient stratification, augmenting the effect of current and emerging therapies, and designing specific treatments to target chemokine pathways, with the aim to reduce melanoma pathogenicity, metastatic potential, and enhance immune cell-mediated cancer killing. The chemokine network may provide selective and specific targets that, if included in current therapeutic regimens, harbour potential to improve outcomes for patients.