BRCA1/2 and TP53 mutation status associates with PD-1 and PD-L1 expression in ovarian cancer

// Verena Wieser 1 , Inge Gaugg 1 , Martina Fleischer 1 , Giridhar Shivalingaiah 2, 5 , Soeren Wenzel 2 , Susanne Sprung 3 , Sigurd F. Lax 4 , Alain G. Zeimet 1 , Heidelinde Fiegl 1 and Christian Marth 1 1 Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck 6020, Austria 2 Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria 3 Institute of Pathology, Medical University of Innsbruck, Innsbruck 6020, Austria 4 Department of Pathology, Hospital Graz Sud-West, Academic Teaching Hospital of the Medical University Graz, Graz 8020, Austria 5 Present address: Division Biological Chemistry, Biocenter, Innsbruck, Medical University of Innsbruck, Innsbruck 6020, Austria Correspondence to: Heidelinde Fiegl, email: Heidelinde.Fiegl@i-med.ac.at Keywords: ovarian cancer; PD-1; PD-L1; IFNγ; BRCA1/2 Received: July 31, 2017 Accepted: February 27, 2018 Published: April 03, 2018 ABSTRACT Checkpoint molecules such as programmed cell death protein-1 (PD-1) and its ligand PD-L1 are critically required for tumor immune escape. The objective of this study was to investigate tumoral PD-1 and PD-L1 mRNA-expression in a cohort of ovarian cancer (OC) patients in relation to tumor mutations. We analyzed mRNA expression of PD-1 , PD-L1 and IFNG by quantitative real-time PCR in tissue of 170 patients with low grade-serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared to 28 non-diseased tissues (ovaries and fallopian tubes) in relation to tumor protein 53 ( TP53 ) and breast cancer gene 1/2 ( BRCA1/2 ) mutation status. TP53 -mutated OC strongly expressed PD-L1 compared to TP53 wild-type OC ( p = 0.028) and BRCA1/2 -mutated OC increasingly expressed PD-1 ( p = 0.024) and PD-L1 ( p = 0.012) compared to BRCA1/2 wild-type OC. For the first time in human, we noted a strong correlation between tumoral IFNG and PD-1 or PD-L1 mRNA-expression, respectively ( p < 0.001). OC tissue increasingly expressed PD-1 compared to healthy controls (vs. ovaries: p < 0.001; vs. tubes: p = 0.018). PD-1 and PD-L1 mRNA-expression increased with higher tumor grade ( p = 0.008 and p = 0.027, respectively) and younger age (< median age, p = 0.001). Finally, in the major subgroup of our cohort, FIGO stage III/IV HGSOC, high PD-1 and PD-L1 mRNA-expression was associated with reduced progression-free ( p = 0.024) and overall survival ( p = 0.049) but only in the univariate analysis. Our study suggests that in OC PD-1 / PD-L1 mRNA-expression is controlled by IFNγ and affected by TP53 and BRCA1/2 mutations. We suggest that these mutations might serve as potential predictive factors that guide anti- PD1 / PD-L1 immunotherapy.