BRCA1/2 and TP53 mutation status associates with PD-1 and PD-L1 expression in ovarian cancer
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Verena Wieser1, Inge Gaugg1, Martina Fleischer1, Giridhar Shivalingaiah2,5, Soeren Wenzel2, Susanne Sprung3, Sigurd F. Lax4, Alain G. Zeimet1, Heidelinde Fiegl1 and Christian Marth1
1Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck 6020, Austria
2Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria
3Institute of Pathology, Medical University of Innsbruck, Innsbruck 6020, Austria
4Department of Pathology, Hospital Graz Süd-West, Academic Teaching Hospital of the Medical University Graz, Graz 8020, Austria
5Present address: Division Biological Chemistry, Biocenter, Innsbruck, Medical University of Innsbruck, Innsbruck 6020, Austria
Heidelinde Fiegl, email: [email protected]
Keywords: ovarian cancer; PD-1; PD-L1; IFNγ; BRCA1/2
Received: July 31, 2017 Accepted: February 27, 2018 Published: April 03, 2018
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.
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