The canonical receptor for complement C5a (C5aR1) has been implicated for a role in promoting tumour growth, but a role for the alternate C5a receptor, C5aR2, in tumour development has not been reported. Thus the present study, compared the roles of C5aR1 and C5aR2 signalling in the B16.F0 murine melanoma model.

B16.F0 tumour cells express both C5aR1 and C5aR2 and signal via ERK and AKT in response to C5a, although no effects on cell proliferation or cell migration were observed in vitro. In accord with previous reports in other murine tumour models, pharmacological blockade of C5aR1 with the C5aR receptor antagonist PMX53, significantly slowed the growth of established B16.F0 tumours, demonstrating the therapeutic potential of C5aR1 inhibition in melanoma.  Tumour growth was also significantly reduced in C5aR1-deficient (C5aR1^-/-) mice, but enhanced in C5aR2^-/- mice.  Given that the B16.F0 tumour cells injected into knockout mice express C5a receptors, the results suggest that the effects of C5aR signalling on tumour growth are indirect, via the host immune response.  This was supported by flow cytometric analysis which showed an increase in tumour infiltrating leukocytes in response to C5aR1 deficiency/antagonism.  While MDSC and Tregs were reduced, CD4⁺ T cells were increased.  Conversely tumour infiltrating leukocyte populations in C5aR2-/- mice were not significantly different from their wild-type counterparts. 

These results demonstrate a role for C5aR1 in promoting B16 melanoma growth, by promoting the generation of MDSC and Tregs and inhibiting effective T cell responses.  They further suggest that C5aR2 may act to moderate the tumour-promoting effects of C5aR1.