PhD Scientific Days 2024

Budapest, 9-10 July 2024

Poster Session J - Pathological and Oncological Sciences 1.

Tissue and Blood Biomarkers of Immunotherapy Resistance in Melanoma

Author(s)

Szonja Anna Kovács1, Tamás Kovács2, András Lánczky1, Ágnes Paál2, Zsombor Hegedűs2, Zoltán Varga2, János Tibor Fekete1, Balázs Győrffy1
1: Department of Bioinformatics, Semmelweis University
2: Department of Pharmacology and Pharmacotherapy, Semmelweis University

Text of the abstract

Introduction: The effectiveness of immune checkpoint inhibitors (ICIs) remains challenging – currently used biomarkers are too ambiguous.
Aims: Our goal was to find new biomarkers of ICI response in melanoma.
Method: We gathered transcriptomic and clinical data from public databases with tumor tissue and blood samples. We used Wilcoxon test and receiver operating characteristics (ROC) analysis for biomarker discovery. The most promising tissue marker with available inhibitor underwent validation both in vitro and in vivo. For cell viability assay, and tumor inoculation we used YUMM1.7 and B16-F10 mouse melanoma cell lines.
Results: Our online platform (www.rocplot.com) hosts data from 1434 tumor tissue- and 843 blood samples. In the melanoma cohort treated with anti-PD1, yes-associated protein 1 (YAP1) was the best druggable candidate, demonstrating overexpression in resistant patients (ROC AUC=0.69, FC=1.8, P=1.1E-08). Higher YAP1 expression corresponded with worse progression-free survival (HR=2.51, P=1.2E-06) and overall survival (HR=2.15, P=1.2E-05). Inhibition of YAP1 with Verteporfin (VP) reduced cell growth after 48 hours, with effects observed at 0.1 µM in both YUMM1.7 (P=0.002) and B16-F10 (P=3.0E-04) compared to vehicle control (n=5-7, one-way ANOVA). In mice bearing YUMM1.7 melanoma, the combination of 50 mg/kg VP with 200 μg anti-PD-1 resulted in tumor size reduction compared to anti-PD-1 (P=0.008) or isotype control (P=0.021) (independent t-test, n=8-10 animals/group). Verteporfin monotherapy did not exhibit superiority over the control group (P=0.42). Furthermore, the combination therapy group showed higher expression of monocyte and T cell markers. Metastasis-related genes, such as Cluster of Differentiation 28 (CD28) (ROC AUC=0.68, FC=1.9, P=3.1E-07), and Matrix Metalloproteinase-9 (MMP9) (ROC AUC=0.70, FC=2.2, P=2.9E-08), exhibited higher expression levels in blood samples from non-responding melanoma patients after immunotherapy treatments.
Conclusions: We established a platform capable of identifying clinically useful biomarkers associated with immune checkpoint inhibitor response.
Funding: PharmaLab RRF-2.3.1-21-2022-00015, KDP-14-3/PALY-2021