Christophe Caux

Unraveling the Tumor Microenvironment and PD-L1 Expression across Tissue Types in High-Grade Serous Ovarian Cancer in the NeoPembrOV/GINECO Phase II Randomized Trial

Abstract Purpose: To describe PD-L1 expression across tissue types and its associated tumor microenvironment and to investigate how it affects its predictive value for response to pembrolizumab in treatment-naïve patients with ovarian cancer included in the NeoPembrOV phase II trial (NCT03275506). Experimental Design: PD-L1 expression was assessed for 85 patients (56 on metastasis and 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 was used as an external validation cohort. Results: PD-L1 was primarily expressed by tumor cells in tubo-ovaries and by ICs in metastases. The IC score assessed on the metastases was associated with a longer progression-free survival in the pembrolizumab arm compared with the control arm. Compared with tubo-ovaries, metastases were enriched in T and B cells as well as in granzyme B (GZMB) CD8 cytotoxic T-cell signatures. In metastases, the IC score was associated with immune infiltration and overexpression of additional immune checkpoints, such as IDO1, LAG3, and ICOS, whereas TPS was associated with cell proliferation, immune infiltration, and IFN-γ pathways. In tubo-ovaries, TPS was associated with pathways linked to cell proliferation and antigen presentation but was depleted in activated immune pathways, and CD274 expression was correlated with hypoxia and PI3K/Akt/mTOR signaling. Conclusions: Distinct PD-L1 expression patterns across tissue types are associated with different biological pathways and tumor microenvironments in ovarian cancer, affecting PD-L1 predictive value. Our results provide novel insights into high-grade serous ovarian cancer biology for tailoring immunotherapy in patients with ovarian cancer.