170P Digital spatial profiling to uncover biomarkers for response prediction in locally advanced gastric cancer patients treated with neoadjuvant chemotherapy

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Background: In the NeoPembrOV phase II trial (NCT03275506) investigating perioperative Pembrolizumab (P) in treatment naïve ovarian cancer (OC) patients, an exploratory analysis found that PD-L1 expression was not associated with benefit from P. Here, we aim to describe PD-L1 expression pattern and the associated TME between tubo-ovary primary localization (PL) and metastases (M) and assess how that impacts PD-L1 predictive value for response to P.Methods: PD-L1 expression was assessed for 85 patients (56 on M, 29 on PL) using the tumor proportion score (TPS) and immune cell (IC) score, considering positivity if 1% (Ventana SP263).RNA sequencing and multiplex immunofluorescence were conducted.The Australian Ovarian Cancer Study (AOCS) served as an external validation cohort.Results: In M, PD-L1 was primarily expressed on ICs with PD-L1 expression restricted to ICs in 48% of PD-L1 positive M samples compared to 17% of PD-L1 positive PL (P ¼ 0.05).In PL, PD-L1 was primarily expressed by tumor cells (TCs).Only IC score assessed on M was associated with PFS benefit with P compared to chemotherapy alone (HR interaction ¼ 0.46 CI95% 0.22-0.96P ¼ 0.04).Compared to PL, M displayed increased density of B cells and an enrichment of gene signature expression for B and T cells including GZMB CD8 cytotoxic T cells (P < 0.05) in the NeoPembrOv and AOCS cohorts.M with IC score 1 showed greater immune infiltrate and overexpressed additional immune checkpoints such as IDO1, LAG3, ICOS compared to IC score negative samples (P < 0.05).In M, the TPS was associated with immune infiltration and interferon-gamma pathway (P < 0.05).In contrast, PL with TPS 1% were depleted in activated immune pathways compared to PD-L1 negative samples.In PL, CD274 correlated with mTORC1 signaling in the NeoPembrOV and AOCS cohorts (spearman r ¼ 0.435 and r ¼ 0.450, respectively).Conclusions: PD-L1 expression differs across tissue type and is associated with different biological pathways and TME impacting PD-L1 predictive value in OC.PD-L1 expression by TCs in PL might promote tumor proliferation and immune escape.Our results provide novel insights into HGSC biology for tailoring immunotherapy in OC patients. Clinical trial identification: NCT03275506.

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