Comparing NK cell profiles within melanoma tumors and pregnancy: Implications for novel immunotherapies - PROJECT SUMMARY: Despite the advent of immune-checkpoint blockade (ICB), melanoma remains a deadly skin cancer. Notably, the indication for ICB therapies continues to expand for melanoma, and they are now used in the adjuvant, neoadjuvant and first-line treatment settings. However, these agents can have deadly side effects and the field remains unable to predict response to these agents. Therefore, refining our ability to predict (A) patients with early-stage disease at high risk of disease progression who would benefit from ICB adjuvant therapy and (B) patients who will not respond to ICB treatment remains a top priority in melanoma, and cancer research more broadly. To address these clinical needs, in this proposal we will study primary tumor invasive capacity to predict risk of progression and tumor immune evasion mechanisms to predict response to ICB therapy. Interestingly, placentation (the formation of the placenta) is a naturally occurring model in which fetal tissue invades into the maternal uterine line (decidua) and evades maternal immune cell destruction. Indeed, there is strong evidence that cancer cells can co-opt mechanisms that evolved for placentation to increase their own malignant potential. The cell type that regulates placentation is called a decidual Natural Killer cell (dNK cell) that, unlike circulating NK cells, is proangiogenic and immunoregulatory. NK cell function is largely regulated by Killer-immunoglobulin like receptors (KIRs) and dNK cells express very high levels of KIRs that bind to HLA-C expressed on invading fetal cells. This interaction promotes tissue invasion and immune evasion during placentation. Importantly, the KIR/HLA-C interaction is highly polymorphic, leading to varied NK cell effector functions across individuals and specific KIR/HLA genotypes are associated with disorders of placentation. Therefore, KIR/HLA genotypes impacting NK cell function within melanoma patient could potentially explain differing therapy responses. Notably, decidual-like NK cells (dl-NK cells) with similar immunosuppressive and proangiogenic functions have been reported in numerous other solid cancers and we have exciting preliminary data showing that these cells are also present within melanoma tumors and express high levels of KIR. Therefore, we hypothesize that the KIR/HLA axis acting on dl-NK cells facilitates both tissue invasion (Aim 1) and immune evasion (Aim 2) in melanoma. To test this hypothesis, we will use state-of-the-art techniques including multiplexed immunohistochemistry, single-cell spatial transcriptomics, patient derived organoid models and high-resolution allelic level sequencing of the KIR/HLA loci, to evaluate these mechanisms. Our primary objective with this proposal is to identify biomarkers that will predict risk of disease progression and response to ICB therapy. Our secondary objective is to define new therapeutic targets to either limit disease progression or improve response to ICB therapy.
