Unlocking the power of immune checkpoint inhibitors: Targeting YAP1 reduces anti-PD1 resistance in skin cutaneous melanoma

Background and Purpose: Immune checkpoint inhibitors, such as anti­PD1, revolutionized melanoma treatment. However, resistance and low response rates remain problems. Our goal was to pinpoint actionable biomarkers of resistance to anti-PD1 treatment and verify therapeutic effectiveness in vivo. Experimental Approach: Using receiver operating characteristic (ROC) and survival analysis in a database of 1434 samples, we identified the strongest resistance-associated genes. Inhibitors were evaluated in C57BL/6J mice using wild-type B16­F10, and BRAF, -PTEN, -CDKN2A-mutant YUMM1.7 melanoma cell lines. We investigated the synergistic impact of anti­PD1 therapy and yes­associated protein 1 (YAP1) inhibition by non-photoactivated Verteporfin. Tumour volume was determined at fixed cutoff points, normalized to body weights. Key Results: In the anti­PD1­treated melanoma cohort, YAP1 was the strongest druggable candidate overexpressed in non­responder patients (ROC AUC = 0.699, FC = 1.8, P=1.1E−8). The baseline YAP1 expression correlated with worse progression-free survival (HR = 2.51, P=1.2E−6, FDR = 1%), and overall survival (HR = 2.15, P = 1.2E−5, FDR = 1%). In YUMM1.7, combination of Verteporfin plus anti-PD1 reduced tumour size more than anti-PD1 monotherapy (P=0.008), or control (P=0.021). There was no difference between the cohorts in B16­F10 inoculated mice. We found increased expression of YAP1 in YUMM1.7 mice compared to B16-F10. The combination therapy induced a more-immune-inflamed phenotype characterized by increased expression of T cell and M1 macrophage markers. Conclusions and Implications: Verteporfin with anti-PD1 exhibited antitumor potential by promoting a pro-inflammatory tumour microenvironment in melanoma. We believe that YAP1 acts as a master regulator of anti-PD1 resistance.