Blockade of CCR5 in melanoma: An alternative immune checkpoint modulator

Abstract

Melanoma is a deadly tumor, which in recent years has been successfully treated with immune checkpoint inhibitors as PD-1/PD-L1 and CTLA-4 inhibitors and targeted therapy as BRAF and MEK inhibitors. However, immunotherapy poses deleterious side effects and pursuit of new therapeutic targets is warranted. As knowledge of tumor immunology advances, such targets are being recognized.C-motif chemokine receptor-5 (CCR5) is a receptor found on immune cells whose effects impact the immune response both to induce inflammation and to activate suppressor cells causing an anti-inflammatory effect. CCR5 is well known as a target for HIV therapy where its blockade is efficient and safe, it is also known that its mutation CCR5delta32 is for the most part non-pathological to its carriers.In oncology, activation of the CCR5 receptor has been observed in high-stage disease and CCR5 blockade has been associated with an increased immune response. In this letter, we build up the rationale to utilize CCR5 as a therapeutic target for metastatic melanoma.

Anti-Cancer Effects of Lactobacillus plantarum L-14 Cell-Free Extract on Human Malignant Melanoma A375 Cells

“…Targeted therapy interferes with mutation of the BRAF gene, which stimulates cells to develop abnormally and divide out of control, but the mutation occurs in around half of all melanoma [19]. In the case of immunotherapy, inflammatory response can be caused in any of the organs of the body [20]. Therefore, the development of new drugs for melanoma is urgently required.…”

The CCL5/CCR5 Axis in Cancer Progression

“…The hypothesis is that CCR5 ligands are involved not only in MDSC recruitment but also in their immunosuppressive polarization [136,137]. Therefore, given that melanoma is highly immunogenic and also immune evasive, inhibiting the CCL5/CCR5 axis with maraviroc was recently proposed as the next step in melanoma immunotherapy [176].…”

The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy

“… 142 The expression of CCR5 stimulates calcium signaling and thus elevates regulatory T cell differentiation and migration to inflammation sites and recent studies suggested that there has profound coaction between CCR5 and immune checkpoints function. 143 , 144 …”