BSBM-14 MOLECULAR PROFILING OF CHECKPOINT LIGANDS AND KEY NK-ACTIVATION AND SUPPRESSIVE LIGANDS BY METASTATIC MELANOMA CELLS

Abstract

Abstract Melanoma is an aggressive skin cancer with high propensity for brain metastasis. For advanced melanoma, immune checkpoint blockade (ICB) drugs, like pembrolizumab, have shown remarkable promise for progression-free survival. The ICB drugs have primarily targeted melanoma suppression of cytotoxic T-lymphocytes (CTLs). Earlier studies showed positive responses in up to 40% of cases, which has improved with discovery of new inhibitory ligands and combination therapy. However, not all patients respond, likely because of the capacity of cancer cells to regulate inhibitory and activating ligands, circumventing both immunomodulatory axes currently targeted by immunotherapies. In this study, we aim to characterize additional axes, prioritizing NK cells of the innate immune system. NK cells can mediate cytotoxic killing similar to CTLs but possess the advantages of germline-encoded receptors that recognize a broad range of ligands, thus, requiring relatively little priming and circumventing antigen escape. We have acquired up to ten patient-derived New Zealand Melanoma lines in collaboration with Auckland Cancer Society Research Centre, of which three are from brain metastases. We used NanoString technology to assess melanoma gene expression of immunoregulatory ligands governing NK activation, inhibition or both (via dual-functional ligands dictated by NK-receptors). The results showed expression of several inhibitory ligands but very few activating ligands. The expression trends were largely similar but varied in a select few ligands. Flow cytometry was used to characterize cell-surface expression of the immunoregulatory proteins. These were compared with the classical inhibitory checkpoint molecules evidencing that melanoma cells expressed more NK inhibitory molecules. We hypothesize that melanoma cells both express inhibitory ligands and suppress activation ligands, to hinder NK cell activity. Here we aim to identify novel immune axes leading towards expansion of ICB therapies. This will afford clinicians a personalized approach and access to combination immunotherapies, especially in combating refractory metastatic melanoma, which have poor prognoses.