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

Abstract 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.