Peripheral blood leukocyte signatures as biomarkers in relapsed ovarian cancer patients receiving combined anti-CD73/anti-PD-L1 immunotherapy in Arm A of the NSGO-OV-UMB1/ENGOT-OV30 trial
Authors: Tandaric Luka , Auranen Annika , Kleinmanns Katrin , DePont Christensen René , Vestrheim Thomsen Liv Cecilie , Wogsland Cara Ellen , McCormack Emmet , Mäenpää Johanna , Madsen Kristine , Stampe Petersson Karen , Raza Mirza Mansoor , Bjørge Line 
Published: October 2024

ABSTRACTBackgroundClinical trials of immune checkpoint inhibitors in epithelial ovarian cancer (EOC) have not shown clear survival benefit, likely due to the complex immunosuppressive mechanisms of the EOC tumor microenvironment. Still, certain patients experience long-term treatment benefit. However, we lack reliable biomarkers for distinguishing dominant immunosuppressive mechanisms and for identifying patients with EOC who are responsive to immunotherapy. The present high-dimensional single-cell study analyzed patients with relapsed EOC enrolled in arm A of the NSGO-OV-UMB1/ENGOT-OV30 trial, wherein the patients underwent combination oleclumab (anti-CD73) and durvalumab (anti-PD-L1) immunotherapy. The objective of the study was the identification of blood-based immunophenotypic signatures conducive to the development of improved strategies for patient selection, response monitoring, and personalized targeting of immunosuppressive mechanisms.MethodsA 40-marker suspension mass cytometry panel was utilized for comprehensive phenotypic and functional characterization of longitudinally sampled peripheral blood leukocytes from patients. Artificial neural network-based unsupervised clustering and manual metacluster curation were used to identify leukocyte subsets for differential discovery and correlation analyses.ResultsAt baseline, short-term and long-term survivors differed with regard to the relative abundances of total peripheral blood mononuclear cells (PBMCs). We observed a significant increase in CD14+CD16−myeloid cells during treatment, initially driven by classical monocyte proliferation and subsequently driven by the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs). This M-MDSC expansion occurred only in patients with shorter progression-free survival, who also showed a continuous decrease in central memory T-cell abundances after baseline. Throughout treatment, we observed upregulation of PD-L1 expression on most T-cell subsets in all patients. Higher expression of CD73 and IDO1 on select leukocyte subsets at baseline was significantly positively correlated with longer progression-free survival.ConclusionsOur study delineates the phenotypic and functional alterations in peripheral blood leukocytes occurring during combination oleclumab/durvalumab immunotherapy in patients with relapsed EOC. We propose a set of biomarkers with potential for treatment personalization and response monitoring: relative abundances of PBMCs at baseline, relative abundances of M-MDSCs and central memory T cells during treatment; PD-L1 expression levels over time; and baseline expression of CD73 and IDO1 on specific leukocyte subsets. However, validation of these biomarkers through larger-scale studies is required.KEY MESSAGESWHAT IS ALREADY KNOWN ON THIS TOPICDespite promising preclinical results and moderate efficacy in lung cancer, combination anti-CD73/anti-PD-L1 immunotherapy in relapsed epithelial ovarian cancer (EOC) has shown only modest response rates, consistent with other EOC immunotherapy trials. Durable clinical benefit remains rare, and there are currently no biomarkers available for the effective selection of EOC patients for personalized immunotherapy and for the characterization of sustained responses.WHAT THIS STUDY ADDSThis study demonstrates that, at baseline of combination anti-CD73/anti-PD-L1 treatment, EOC patients with higher relative abundances of peripheral blood mononuclear cells (PBMCs) and elevated expression of CD73 and IDO1 on certain PBMC subsets may experience greater overall survival and progression-free survival benefit, respectively. Additionally, patients with faster disease progression exhibited a shift in CD14+CD16−myeloid cells towards a more immunosuppressive phenotype and had lower abundances of central memory T cells over time compared to patients with slower progression, while PD-L1 expression increased significantly over time on T cells of all patients, regardless of the rate of disease progression.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYWhile further clinical validation is required, we propose blood-based biomarkers for predicting and monitoring responses to immunotherapy in EOC, aiming to guide future research on immunotherapy resistance mechanisms and treatment personalization, with a focus on specific peripheral leukocyte subsets.