O14 Monocytes and macrophages in the melanoma tumour microenvironment express Fc receptors which can be engaged with monoclonal antibodies of different isotypes

Abstract Introduction and aims Melanoma is the deadliest form of skin cancer and has an increasing worldwide incidence. It is well established that the melanoma tumour microenvironment (TME) has a large immune cell infiltrate, including a prominent monocytic compartment. Monocytic cells within the TME support melanoma growth, survival and metastasis. Contrastingly, such cells can be stimulated to promote tumour killing when engaged with monoclonal antibodies (mAbs) against cancer antigens, owing to their expression of multiple Fc receptors (FcRs). However, little is known about the monocytic subsets present within melanoma, the FcRs they express and how engaging their FcRs may influence function. Methods Flow cytometry on peripheral monocytes isolated from patients with melanoma and healthy volunteers enabled the characterization of cell surface markers. Next, publicly available single-cell RNA-Seq datasets were analysed to explore the transcriptome of melanoma-associated macrophages and these phenotypes were recapitulated in vitro. Finally, monocytes and macrophages were cocultured with melanoma cells, with or without the addition of mAbs against a melanoma antigen, in order to assess the effect of FcR crosslinking on monocyte and macrophage phenotype and function. Results Circulating monocytes in patients with melanoma feature an inhibitory phenotype, and express multiple FcRs, including Fcε and Fcγ receptors, which could be targeted with mAbs of multiple isotypes. Secondly, monocytic cells within the melanoma TME express protumour genes, including metalloproteinases and angiogenic factors. However, FcR expression suggests that tumour-promoting subsets can be targeted with mAbs. Finally, in ex vivo cocultures with melanoma cells, the FcRs of both human monocytes and macrophages are able to engage antimelanoma mAbs of multiple isotypes, inducing differential phenotype change. This is demonstrated by the upregulation of activation markers and costimulatory cell surface markers. Conclusions Together, these data suggest that tumour-promoting monocytic cells within the melanoma TME can be engaged and harnessed using different isotypes of mAbs targeting melanoma.