PD-L1 Expression on Circulating Tumour-Derived Microvesicles as a Complementary Tool for Stratification of High-Grade Serous Ovarian Cancer Patients

Abstract

Background: Ovarian cancer (OC) has recently attracted attention for the use of PD-1/PD-L1 axis blocking agents, with durable activity reported only in a subset of patients. The most used biomarker for sensitivity to the PD-1/PD-L1 axis blockade is tumour PD-L1 status by immunohistochemistry. However, patient stratification using this method suffers from intrinsic heterogeneity of OC, likely contributing to the unsatisfactory results obtained so far. Cells communicate with each other by releasing microvesicles (MVs) that carry parental cell surface features. Thus, we hypothesised that PD-L1+ tumour cells (TC) and infiltrating PD-L1+ leukocytes should shed MVs carrying surface PD-L1 that may serve as a proxy for the whole tumour PD-L1 status. Results: We showed for the first time the presence of measurable amounts of TC- and leukocyte-derived PD-L1+ MVs (range: 1.4–178.8 MVs/μL and 6.2–504.8 MVs/μL, respectively) in the plasma of high-grade serous OC (HGSOC) patients (n = 63), using a sensitive flow cytometry platform. The concentration of PD-L1+ MVs of either origin did not associate with the PD-L1 status of TCs and leukocytes in the tumour biopsies, suggesting that the circulating PD-L1+ MVs also included ones from locations not selected for immunohistochemistry analysis and represented the PD-L1 status of the whole tumour mass. In this study, we also describe the serendipitous discovery of circulating PD-L1+ MVs of platelet origin (10.3–2409.6 MVs/μL). Conclusions: The enumeration of circulating PD-L1+ MVs in HGSOC patients may provide a novel direction for assessing the tumour PD-L1 status and contribute to HGSOC patient stratification for immunotherapy interventions. The presence of circulating PD-L1+ MVs of platelet origin, a finding not yet reported in HGSOC patients, warrants further studies.

Interactions between Platelets and Tumor Microenvironment Components in Ovarian Cancer and Their Implications for Treatment and Clinical Outcomes

“…Platelets promote the exhaustion of CD4 + T helper and CD8 + cytotoxic T cells [321] in conjunction with Tregs and Bregs [363]. Moreover, platelets promote the expression of immune checkpoint molecules on ovarian cancer cells, which further supports cancer progression [14] and can affect patients' responses to immunotherapies [307,364].…”

“…Ovarian tumors display the Treg hi phenotype [278,306], which may explain ovarian cancer patients' unsatisfactory responses to immune checkpoint inhibitors. In many cancers, PD-L1-containing platelet microparticles adhere to PD-1 on Tregs and induce immune tolerance [307]. The simultaneous inhibition of the CXCR4-SDF-1 and PD-1-PD-L1 pathways and the depletion of effector Tregs may enhance the antitumor immune response and reduce mortality in ovarian cancer patients [242,308].…”

PD-L1 Expression in Different Segments and Histological Types of Ovarian Cancer According to Lymphocytic Infiltrate

“…PD-1/PD-L1 target therapy has recently attracted attention in EOC [2]. The efficiency of immunotherapy is based on the presence of target molecules that could be modulated by different therapeutic agents.…”

“…In HGSC at least four genomic classes were identified differing for immunoreactivity [31,32]. Therefore, a comprehensive analysis of the genomic status of EOC and immunological characteristics in the tumor microenvironment could be predictive factors for immune therapy response [2,32]. We believe that additional analysis of interactive signaling pathways could improve strengthen of PD-L1 inhibitors.…”

“…Platinumbased chemotherapy is the main treatment for these patients. Despite new therapy, such as vascular endothelial growth factor (VEGF) and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences are still inevitable [2].…”