Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients

Abstract

Although circulating tumor cells (CTCs) have potential as diagnostic biomarkers for cancer, determining their prognostic role in cancer patients undergoing treatment is a challenge. We evaluated the prognostic value of programmed death-ligand 1 (PD-L1) expression in CTCs in colorectal and prostate cancer patients undergoing treatment. Peripheral blood samples were collected from 62 metastatic colorectal cancer patients and 30 metastatic prostate cancer patients. CTCs were isolated from the samples using magnetic separation with the cell-surface vimentin(CSV)-specific 84-1 monoclonal antibody that detects epithelial-mesenchymal transitioned (EMT) CTCs. CTCs were enumerated and analyzed for PD-L1 expression using confocal microscopy. PD-L1 expression was detectable in CTCs and was localized in the membrane and/or cytoplasm and nucleus. CTC detection alone was not associated with poor progression-free or overall survival in colorectal cancer or prostate cancer patients, but nuclear PD-L1 (nPD-L1) expression in these patients was significantly associated with short survival durations. These results demonstrated that nPD-L1 has potential as a clinically relevant prognostic biomarker for colorectal and prostate cancer. Our data thus suggested that use of CTC-based models of cancer for risk assessment can improve the standard cancer staging criteria and supported the incorporation of nPD-L1 expression detection in CTCs detection in such models.

Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

“…Although there is discordance in the literature regarding expression and prognostic value of PD-L1 in CTCs, our results are more in line with our understanding of PD-L1 expression and prognostic significance in tumor biopsies (24,(47)(48)(49). Initial research on PD-L1 in CTCs has given conflicting results based on our understanding of the PD-L1 cascade.…”

“…These conclusions are in contrast with general IHC testing of primary tumor masses, which finds little to no correlation between PD-L1 expression in biopsies and survival, when PD-L1/PD-1 therapeutics are not used (29-31, 36-41, 46). Furthermore, only a small fraction of patients will actually respond to PD-L1/PD-1 therapy, indicating that the reported CTC assays may be overly sensitive for detecting PD-L1 and will unlikely translate to clinical benefit for PD-L1/PD-1 therapies (16,(47)(48)(49)). An alternative issue may be that many CTC technologies do not differentiate the EMTCTC subpopulation from the CellSearch CTC population (i.e., PDCTCs), or make any mention of CStCs (3,4,6,7,16,17,(47)(48)(49).…”

“…This discrepancy may be attributed to the dynamic nature of immune modulation expression and/or the inability to analyze the stromal cell components. Because immune checkpoint protein expression is dynamic, being influenced by multiple microenvironmental, inflammatory, and therapy factors, it has been hypothesized that blood-based analysis may provide a more accurate representation of the current PD-L1 expression in patients (29,30,39,42,43,47,48). Interestingly, we found three classes of PD-L1 responses in the circulating cells of patients, those that are persistently low, persistently high, or inducible from low to high, which occurs in about one-third of patients (32%).…”

“…Initial research on PD-L1 in CTCs has given conflicting results based on our understanding of the PD-L1 cascade. In some cases, all patients' CTCs had positive PD-L1 (47); further presence of PD-L1 on CTCs has been identified as a general prognostic indicator of survival (16,48). These conclusions are in contrast with general IHC testing of primary tumor masses, which finds little to no correlation between PD-L1 expression in biopsies and survival, when PD-L1/PD-1 therapeutics are not used (29-31, 36-41, 46).…”

PD‐L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation

“…Very recently, this phenomenon has been appreciated by Satelli et al 28. as they have found a significant correlation between nuclear PD‐L1 in breast cancer and poor prognosis.…”