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.
Highlights
Ovarian cancer (OC) is the major cause of death among gynecological cancer entities [1]
We found that tumor protein 53 (TP53) and breast cancer gene 1/2 (BRCA1/2) mutated OC was associated with high programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) expression
We noted that young women and patients with advanced OC exhibited increased expression of PD-1 and PD-L1 which was associated with poor clinical outcome
Summary
Ovarian cancer (OC) is the major cause of death among gynecological cancer entities [1]. Multidisciplinary treatment options including surgery, chemotherapy regimens and anti-angiogenic agents have considerably evolved [2], long term prognosis for OC patients remains devastating [3]. Therapies targeting tumor immunogenicity and anti-tumor immunity [4] such as antibodies that inhibit checkpoint molecules, i.e. www.oncotarget.com the programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway [5] have recently gained attention as a novel therapeutic option in OC [6]. Checkpoint (i.e. PD-1/ PD-L1) inhibitors can restore T-cell mediated tumor immunogenicity and have been successfully established in anti-tumor treatment [9]. Ongoing clinical trials investigate whether PD-1/PD-L1 inhibitors can be an effective treatment option for patients with OC
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