Sponsor: Deutsche Krebshilfe

Melanomas are malignant tumors arising as a consequence of UV-induced genomic DNA damage in pigment producing melanocytes of the skin. UV-induced inflammatory responses promote the proliferation of malignant cells and foster their migratory behavior, their invasive growth and their ability to establish metastases in other tissues (Bald…Tüting, Nature 2014). Most melanomas are detected at an early stage and can be cured by surgical resection. However, some patients develop metastases in internal organs which has led to their death in almost all cases. Recently, novel targeted signal transduction inhibitors and immune check-point modulators have been introduced into clinical practice, which can stabilize the disease course in many patients and even cause long-term tumor regression in some patients. Overcoming primary and secondary therapy resistance represents the major challenge in this highly active area of research. The oncolytic virus T-VEC, which has recently been approved for the treatment of melanoma metastases by the FDA, is considered as an attractive possibility for future innovative combination therapies. Oncolytic viruses are thought to work by preferentially infecting and lysing tumors and thereby stimulating antitumor immunity. Tumor cell infection and lysis is known to be limited by type I interferons, and melanomas have been suggested to vary in their type I IFN responsiveness for poorly understood reasons. In our preliminary experiments we made the unexpected observation that melanoma cell responsiveness to type I IFNs was inversely correlated with their melanocytic differentiation state. The principal goal of this research project is to test the hypothesis, that an oncolytic infection and lysis is especially effective for differentiated melanoma cells and that this contributes to the activation of a cytotoxic T and NK-cell response against these frequently immune cell poor tumors. The resulting anti-tumoral immunity can then be further enhanced by blocking immunoregulatory PD1/PD-L1 interactions. In the first part of the project we will use an expanded panel of selected human melanoma cells to further investigate the potential inter-connection between the melanoma cell differentiation status, the type I IFN responsiveness and the sensitivity for infection with the type I IFN sensitive oncolytic virus SFV VA7 in vitro. Using this information we will attempt to unravel the mechanisms underlying the cell state-dependent type I IFN responsiveness and susceptibility to oncolytic infection. In the second part of the project we will address these aspects in vivo in the genetic HGF-CDK4(R24C) mouse melanoma model developed in our laboratory. We will explore the ability of oncolytic immuno-virotherapy to preferentially target poorly type I IFN responsive, differentiated melanomas and sensitize them to immune check-point blockade. The proposed project will contribute to our mechanistic understanding of oncolytic virotherapy as part of novel combination therapies for patients with advanced melanoma. This has important therapeutic implications for the stratification and development of personalized cancer treatment approaches.