The clinical implication of soluble PD-L1 (sPD-L1) in patients with breast cancer and its biological function in regulating the function of T lymphocyte

Abstract

This work investigated the clinical prognostic implications and biological function of plasma soluble programmed cell death ligand 1 in breast cancer patients. Plasma sPD-L1 levels of recurrent/metastatic breast cancer patients were determined, and the association of sPD-L1 levels and metastatic progression-free survival and metastatic overall survival was assessed. The PD-L1 expression on breast cancer cells was analyzed by flow cytometry, and the level of sPD-L1 in the supernatant of breast cancer cells was determined by enzyme-linked immunosorbent assay. Furthermore, the effect of sPD-L1 on the proliferation and apoptosis of T lymphocytes was detected by WST-1 assay and flow cytometry. The plasma sPD-L1 levels in 208 patients with recurrent/metastatic breast cancer before receiving first-line rescue therapy were measured. The optimal cutoff value of plasma sPD-L1 for predicting disease progression was 8.774 ng/ml. Univariate and multivariate analyses identified high sPD-L1 level (≥ 8.774 ng/ml) and visceral metastasis were independent factors associated with poor prognosis. Relevance analysis showed that the plasma sPD-L1 level was weaklyassociated with some systemic inflammation markers, including white cell count (WBC), absolute monocytecount, and absolute neutrophil count. Furthermore, we found sPD-L1 could be found in supernatant of culture with breast cancer cell line expressing PD-L1 on the cell surface and inhibit T lymphocyte function, playing a negative regulatory role in cellular immunity. sPD-L1 was a good tumor predictive maker in breast cancer and it may play a potentially important role in immune tolerance.

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

“…In this study, native human sPD-L1 was found to induce suppressive effects on activated T-cells, thus mimicking the effect of mPD-L1 [ 128 ]. A recent study using sPD-L1 isolated from the plasma of patients with recurrent/metastatic breast cancer demonstrated that sPD-L1 can inhibit T lymphocyte function, acting as a negative regulatory element in cellular immunity [ 129 ]. Similar observations have been reported previously in experimental (in vitro) studies using sPD-L1 released from lung cancer cells [ 130 ].…”

Refining patient selection for breast cancer immunotherapy: beyond PD-L1

“…141 PD-L1 can also be found as in patients' plasma. A recent study by Han et al, 142 on 208 patients with recurrent/ metastatic BC before receiving first-line therapy, showed that high soluble PD-L1 level (8.774 ng/ml) and visceral metastasis were independent factors associated with poor prognosis. Both exosomal and soluble PD-L1 seem to properly reflect the level of the patient immunosuppressive state.…”

Currently Used Laboratory Methodologies for Assays Detecting PD-1, PD-L1, PD-L2 and Soluble PD-L1 in Patients with Metastatic Breast Cancer

“…For plasma samples, lithium heparin BD blood collection vials were used and promptly centrifuged within 4 h to obtain fresh plasma. The plasma specimens were stored at −80 • C until testing [47]. In general, the processing time and storage conditions of blood samples are critical for the stable and reliable measurement of target analytes [61].…”

“…Soluble PD-L1, which can attach to PD-1, is usually generated following proteolytic cleavage of membrane-bound PD-L1 by translation of alternatively spliced mRNA or matrix metalloproteinase [76]. Soluble PD-L1 has been reported to be a potential prognostic predictor in several cancers [47]. Soluble PD-L1 indicates an anti-immune response and cooperatively affects tumor progression.…”

“…Regarding immunotherapy, therapeutic anti-PD-L1 might be absorbed by soluble PD-L1 before reaching TC, which alters the killing effect of BC cells on IC [60]. Meanwhile, a specific anti-PD-L1 antibody agent might suppress the expression of soluble PD-L1 and remove its blocking effect on the PD-1 negative signaling pathway, leading to improving T cell viability and enhancing the killing of BC cells [47]. There have been several studies investigating soluble PD-L1 because abnormalities in this factor are involved in early and long-term immune modulation.…”