Unravelling the tumor microenvironment and PD-L1 expression across tissue type in high-grade serous ovarian cancer in the NeoPembrOV/GINECO phase II randomized trial

Purpose: To describe PD-L1 expression across tissue types and its associated tumor microenvironment (TME) and to investigate how it impacts its predictive value for response to pembrolizumab in treatment-naïve ovarian cancer (OC) patients included in the NeoPembrOV phase II trial (NCT03275506). Methods: PD-L1 expression was assessed for 85 patients (56 on metastasis, 29 on tubo-ovary) using tumor proportion score (TPS) and immune cell (IC) score, considering positivity if ≥ 1% and high expression if ≥ 5%. RNA sequencing and multiplex immunofluorescence were conducted. The Australian Ovarian Cancer Study (AOCS) was used as an external validation cohort. Results: PD-L1 was primarily expressed by tumor cells (TCs) in tubo-ovaries and by ICs in metastases. IC-score assessed on the metastases was associated with a longer PFS in the pembrolizumab arm compared to the control arm. Compared to tubo-ovaries, metastases were enriched in T and B cells as well as in GZMBCD8 cytotoxic T cell signatures. In metastases, IC-score was associated with immune infiltration and overexpression of additional immune checkpoints such as IDO1, LAG3, ICOS while TPS was associated with cell proliferation, immune infiltration and interferon-gamma pathways. In tubo-ovaries, TPS was associated with pathways linked to cell proliferation and antigen presentation but depleted in activated immune pathways, and CD274 expression was correlated with hypoxia and PI3K/Akt/mTOR signaling. Discussion: Distinct PD-L1 expression patterns across tissue type are associated with different biological pathways and TME in OC impacting PD-L1 predictive value. Our results provide novel insights in HGSC biology for tailoring immunotherapy in OC patients.