Tankyrase Inhibition in Metastatic Melanoma Immunotherapy

Immunotherapy with immune checkpoint inhibitors has transformed the treatment landscape for melanoma. However, a significant portion of patients (40-65%) do not respond to this therapy due to resistance mechanisms, particularly those driven by the WNT/ß-catenin cell signaling pathway. This resistance, associated with the ß-catenin protein in 42% of skin melanoma cases, currently lacks effective targeted treatments. At Oslo University Hospital, researchers have developed promising tankyrase inhibitors that block WNT/ß-catenin signaling, potentially overcoming this resistance. Preliminary studies indicate that inhibiting tankyrase can elevate levels of MITF, a protein crucial for activating immune responses against melanoma. Increased MITF levels enhance tumor antigen presentation, which boosts immune cell activity and strengthens the efficacy of immunotherapy. This research aims to elucidate how tankyrase inhibition can enhance immune responses in melanoma treatment.

40-65% of melanoma patients do not respond to immune checkpoint inhibitor (ICPi) therapy. Resistance mechanisms are currently being mapped, and cellular signaling pathways, such as YAP and WNT/ß-catenin signaling, emerge as promising targets for therapeutical intervention. ß-catenin is the key transcriptional regulator of WNT/ß-catenin signaling, and ß-catenin-induced immune evasion is found in 42% of cutaneous melanoma. Currently, there are no therapeutical strategies available for targeting WNT/ß-catenin signaling to counteract ICPi resistance in melanoma. At Oslo University Hospital we have discovered a higly potent and specific preclinical stage tankyrase inhibitors (TNKSi, OM-153 and OM-0815). To our knowledge, OM-153/OM-0815 are leading the field for its bio-target and for a therapeutic WNT/ß-catenin signaling inhibitor. In a recent publication, using TNKSi-mediated blockade of WNT/ß-catenin signaling, we uncover a novel combinatorial therapeutical strategy to overcome ß-catenin-mediated resistance to ICPi therapy in melanoma. However, the precise mechanism behind TNKSi-mediated regulation of immune regulation and control of susceptibility to ICPi therapy is not properly characterized. We have recently discovered that TNKSi can induce accumulation of MITF in murine melanoma tumors. MITF is a central transcription factor involved in melanoma phenotype-switching and antigen presentation. MITF stabilization can lead to altered antigen presentation, PD-L1 expression, cytokine release, immune cell infiltration, enhanced CD8+ T cell cytotoxicity and increased sensitivity to immune checkpoint inhibition. WNT/ß-catenin and YAP signaling are central regulators of MITF expression. Our initial efficacy data point towards a beneficial stimulation of the tumor-immune cell interplay resulting in an adaptive immune response targeting tumors. In this project we propose to use test TNKSi/ICPi in a broad spectrum of immune competent mouse models for detailed mechanistic studies