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

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 <i>PD-1</i> and <i>PD-L1</i> mRNA-expression in a cohort of ovarian cancer (OC) patients in relation to tumor mutations. We analyzed mRNA expression of <i>PD-1</i>, <i>PD-L1</i> and <i>IFNG</i> 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 (<i>TP53</i>) and breast cancer gene 1/2 (<i>BRCA1/2</i>) mutation status. <i>TP53</i>-mutated OC strongly expressed <i>PD-L1</i> compared to <i>TP53</i> wild-type OC (<i>p</i> = 0.028) and <i>BRCA1/2</i>-mutated OC increasingly expressed <i>PD-1</i> (<i>p</i> = 0.024) and <i>PD-L1</i> (<i>p</i> = 0.012) compared to <i>BRCA1/2</i> wild-type OC. For the first time in human, we noted a strong correlation between tumoral <i>IFNG</i> and <i>PD-1</i> or <i>PD-L1</i> mRNA-expression, respectively (<i>p</i> < 0.001). OC tissue increasingly expressed <i>PD-1</i> compared to healthy controls (vs. ovaries: <i>p</i> < 0.001; vs. tubes: <i>p</i> = 0.018). <i>PD-1</i> and <i>PD-L1</i> mRNA-expression increased with higher tumor grade (<i>p</i> = 0.008 and <i>p</i> = 0.027, respectively) and younger age (< median age, <i>p</i> = 0.001). Finally, in the major subgroup of our cohort, FIGO stage III/IV HGSOC, high <i>PD-1</i> and <i>PD-L1</i> mRNA-expression was associated with reduced progression-free (<i>p</i> = 0.024) and overall survival (<i>p</i> = 0.049) but only in the univariate analysis. Our study suggests that in OC <i>PD-1</i>/<i>PD-L1</i> mRNA-expression is controlled by <i>IFNγ</i> and affected by <i>TP53</i> and <i>BRCA1/2</i> mutations. We suggest that these mutations might serve as potential predictive factors that guide anti-<i>PD1</i>/<i>PD-L1</i> immunotherapy.