Modulation of innate immunity in the tumor microenvironment.

A recent report from the Center for Disease Control identified melanoma as being among the highest causes of cancer-related mortalities in the USA. While interventions such as checkpoint blockade have made substantial impact in terms of improving response rates and overall survival, a significant number of patients fail to respond to treatment or become resistant to therapy. A better understanding of the tumor microenvironment in these patients becomes imperative for identifying immune suppressive mechanisms that impact the development of effective anti-tumor immune responses. We have investigated innate immune cells (dendritic cells, NK cells) in the tumor microenvironment (TME) in order to devise effective targeted anticancer immune therapies. We find that matrix metalloproteinase-2 (MMP-2), secreted from melanoma cells and stromal cells, cleaves IFNAR1 and stimulates TLR-2 on dendritic cells (DC) within the TME. Both these events independently culminate in programing the DCs to promote pro-tumorigenic TH2 T cell differentiation. In addition, we have shown that NK cells become functionally exhausted in melanoma patients. We identified the expression of Tim-3 as one of the factors responsible for NK cell exhaustion and showed that anti-Tim3 antibodies partially reversed this exhaustion. We have initiated local intervention strategies such as intra-tumoral administration of DC activating Poly-ICLC and compared the efficacy of different TLR agonists and melanoma antigens for use as combination tumor vaccine in clinical trials. Such approaches will provide a unique insight into tumor biology and will facilitate in development of highly effective and cell type-specific immune therapies.