Abstract C057: Tankyrase Inhibition Reprograms Melanoma Metastases to Overcome Resistance to PD-1 Blockade

Abstract Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have transformed melanoma treatment, but many tumors remain non-responsive, in part due to immune exclusion driven by canonical WNT/β-catenin signaling. To overcome this resistance, we evaluated the tankyrase 1/2 inhibitor OM-153, which suppresses WNT/β-catenin and Yes-associated protein (YAP) signaling, in combination with anti-PD-1 in immunocompetent melanoma models. Melanoma lung metastases were established in a syngeneic in vivo model using the B16-F10 cell line and treated with anti-PD-1, OM-153 or combination therapy. An efficacy study using bioluminescence imaging showed a significant reduction in tumor burden only in the combination group compared to control. To further explore the underlying cellular mechanisms in the metastatic niche, we performed single-cell RNA sequencing to characterize treatment-dependent changes, revealing altered differentiation states of melanoma metastases in the OM-153 and combination treatment groups. Consistent with these findings, we observed upregulation of microphthalmia-associated transcription factor (MITF) in OM-153-treated groups. MITF stabilization has previously been linked to altered antigen presentation, PD-L1 expression, cytokine release, immune cell infiltration, enhanced CD8+ T cell cytotoxicity, and increased sensitivity to immune checkpoint inhibition. In parallel, to define OM-153-specific effects, B16-F10 cells were treated in vitro with OM-153 and analyzed by bulk RNA sequencing and quantitative proteomics. OM-153 induced broad transcriptional and proteomic remodeling of pathways associated with WNT/β-catenin, Hippo, PI3K, and Notch signaling, as well as antigen presentation and cytokine and chemokine networks. Notably, OM-153 enhanced signaling driven by the key melanoma transcription factor MITF, and complementary experiments demonstrated increased nuclear MITF localization following treatment. Together, these findings identify MITF as a potential key regulator of OM-153-induced programs and position OM-153 as a mechanistically targeted partner for PD-1 blockade. This suggests that tankyrase inhibition can reprogram melanoma cells and the tumor microenvironment to overcome checkpoint inhibitor resistance. Generative artificial intelligence-based tools were used for language editing (grammar and punctuation) of this abstract. Citation Format: Ole Vidhammer Bjørnstad, Maureen Tania Meling, Shoshy Alam Brinch, Therese Bang, Maria Candamo-Lourido, Martin Frank Strand, Ingrid Lofthus Morken, Karl Martin Forbod, Ida Johnsen, Nann Louise Kristoffersen, Sandra Espada Serrano, Clara Hammarstrøm, Alexandre Corthay, Inger Øynebråten, Román Martí-Díaz, José Neptuno Rodriguez López, Peter Olaf Hofgaard, Ranveig Braathen, Eivind Hovig, Gunhild Mari Mælandsmo, Sigurd Læines Bøe, Hideo Yagita, Jo Waaler. Tankyrase Inhibition Reprograms Melanoma Metastases to Overcome Resistance to PD-1 Blockade [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C057.