The impact of the complement receptors C3aR1 and C5aR1 on the progression of melanoma

Abstract

Melanoma is an aggressive skin cancer that develops from the malignant transformation of pigment-producing skin cells, melanocytes. The incidence of cutaneous melanoma is remarkably high, with an estimated number of new cases in the United States in 2022 close to 100,000 patients. Several previous reports pointed out the effect of the complement system in the progression of melanoma, although the precise mechanism is largely unknown. The complement system is a crucial component of innate immunity, and it also has a significant role in adaptive immunity regulating the function of immune cells. The complement receptors C3aR1 and C5aR1 are present on the surface of various immune cells. Anaphylatoxins (C3a and C5a) generated by complement activation bind to their respective receptors, C3aR1 and C5aR1, suppress the antitumor function of immune cells and promote migration and activity of immunosuppressive cells in the tumor microenvironment. Hence, C3aR1 and C5aR1 act as immune checkpoint receptors. To identify the precise role of the complement receptors in melanoma, we challenged C3 −/−, C3aR1 −/−, and C5aR1 −/−mice with the B16F10 murine melanoma cells. We showed that the deficiency of these molecules substantially delayed tumor growth and promoted an antitumorigenic immune response. The results of this study indicate the distinct role of complement receptor signaling on melanoma growth and suggest a novel immunotherapeutic approach. Developmental Research Program Award from the MD Anderson Melanoma SPORE (P50CA221703-04)