The interaction of programmed cell death 1 ligand 1 (PDL1) with its receptor programmed cell death 1 (PD1) inhibits T cell responses, and blockade of this interaction has proven to be an effective immunotherapy for several different cancers. PDL1 can be expressed on the surface of tumour cells, immune cells and other cells in the tumour microenvironment but is also found in extracellular forms. Recent studies have explored the importance of different forms of extracellular PDL1, such as on exosomes or as a freely soluble protein, and have shown that PDL1-expressing exosomes can inhibit antitumour immune responses. In patients with melanoma, exosomal PDL1 is also a marker of immune activation early after initiation of therapy with PD1-blocking antibodies and predicts a clinical response to PD1 blockade. In this Progress article, we highlight recent insights into the role of exosomal PDL1 in immune oncology and how it may be useful as a biomarker for the management of cancer or to define a subset of patients who would benefit from therapeutics that block exosome production. Freeman and colleagues draw our attention to the existence of different forms of PDL1 — cell bound and various extracellular forms. Recent studies show that PDL1 on exosomes can inhibit antitumour immune responses and may be a useful biomarker for the management of cancer immunotherapy.

The importance of exosomal PDL1 in tumour immune evasion

Abstract Endometrial cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states. Current models do not adequately reflect oncogenic origin and pathological progression in patients. Here we use single-cell RNA sequencing to profile cells from normal endometrium, atypical endometrial hyperplasia, and endometrioid endometrial cancer (EEC), which altogether represent the step-by-step development of endometrial cancer. We find that EEC originates from endometrial epithelial cells but not stromal cells, and unciliated glandular epithelium is the source of EEC. We also identify LCN2 + /SAA1/2 + cells as a featured subpopulation of endometrial tumorigenesis. Finally, the stromal niche and immune environment changes during EEC progression are described. This study elucidates the evolution of cell populations in EEC development at single-cell resolution, which would provide a direction to facilitate EEC research and diagnosis. 

/pdf/single-cell-transcriptomic-analysis-highlights-origin-and-35ptvxxs.pdf

Single-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma

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 weakly associated with some systemic inflammation markers, including white cell count (WBC), absolute monocyte count, 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.

/pdf/the-clinical-implication-of-soluble-pd-l1-spd-l1-in-patients-308cvexb8r.pdf

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

OBJECTIVE
The pathophysiological mechanisms of idiopathic pulmonary fibrosis (IPF) are not well elucidated. It is assumed that oxidative stress and inflammation are the key underlying culprits for its onset and progression. To gain deeper insight into these processes, we have evaluated several oxidative stress parameters, inflammation markers [i.e., high sensitivity C-reactive protein (hsCRP), serum amyloid A1 (SAA1)], soluble programmed cell death-ligand 1 (sPD-L1), and 25-hydroxyvitamin D [25(OH)D] in IPF patients.


PATIENTS AND METHODS
Biochemistry analyses were done in 30 consecutive IPF patients and 30 age and gender-matched healthy control group (CG).


RESULTS
IPF patients had significantly higher advanced oxidation protein products (p<0.001), pro-oxidant-antioxidant balance (p=0.010), total oxidative status (p<0.001), and ischemia modified albumin (p<0.001) compared to CG. Lower total antioxidant status and total sulfhydryl groups (tSGH) and significantly higher sPD-L1, hsCRP (p<0.001 for all), SAA1 proteins (p=0.014) and [25(OH)D] severe deficiency [11.0 (9.6-15.1) nmol/L] in IPF patients compared to CG were observed. Paraoxonase 1 activity and hsCRP level were lower, while tSHG and sPD-L1 were higher in IPF patients with more severe disease (i.e., II+III stage compared to I stage, p<0.05 for all).


CONCLUSIONS
IPF patients are in a state of profound oxidative stress compared to healthy people. The inflammatory component of the disease was confirmed by higher hsCRP and SAA1, but lower [25(OH)D] in IPF than in healthy people. Also, higher levels of sPD-L1 in patients with IPF compared to healthy individuals suggest that sPD-L1 may have a significant role in immune response in IPF.

Oxidative stress and inflammation parameters-novel biomarkers for idiopathic pulmonary fibrosis.

Previous studies have shown clinical relevance of programmed death-ligand 1 (PD-L1) and soluble PD-L1 (sPD-L1) in human cancers. However, still contradictory results exist. Our aim was evaluation of PD-L1-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), monocytes/macrophages (MO/MA), tumour cells (TC) and immune/inflammatory cells (IC) as well as investigation of the sPD-L1 in ovarian cancer (OC) patients. The group of 74 pretreatment women were enrollment to the study. The expression of PD-L1 on M-MDSCS and MO/MA was assessed by flow cytometry. The profile of sPD-L1 was examined with ELISA. The expression of PD-L1 in mononuclear cells (MCs) was analyzed using real time PCR. PD-L1 immunohistochemical analysis was prepared on TC and IC. An in silico validation of prognostic significance of PD-L1 mRNA expression was performed based microarray datasets. OC patients had significantly higher frequency of MO/MA versus M-MDSC in the blood, ascites and tumour (each p   0.05). Significantly higher accumulation of blood-circulating M-MDSC, MO/MA, PD-L1+M-MDSC, PD-L1+MO/MA and sPD-L1 was observed in patients versus control (p   0.05). The expression of PD-L1 was significantly higher on IC versus TC (p   0.05) except higher level of PD-L1+TC in the endometrioid versus mucinous tumours. Interestingly, blood-circulating sPD-L1 positively correlated with PD-L1+M-MDSCs (p = 0.03) and PD-L1+MO/MA (p = 0.02) in the blood but not with these cells in the ascites and tumours nor with PD-L1+TC/IC (each p > 0.05). PD-L1 and sPD-L1 were not predictors of overall survival (OS; each p > 0.05). Further validation revealed no association between PD-L1 mRNA expression and OS in large independent OC patient cohort (n = 655, p > 0.05). Although PD-L1 may not be a prognostic factor for OC, our study demonstrated impaired immunity manifested by up-regulation of PD-L1/sPD-L1. Furthermore, there was a positive association between PD-L1+ myeloid cells and sPD-L1 in the blood, suggesting that sPD-L1 may be a noninvasive surrogate marker for PD-L1+myeloid cells immunomonitoring in OC. Overall, these data should be under consideration during future clinical studies/trials.

/pdf/accumulation-of-blood-circulating-pd-l1-expressing-m-mdscs-3gppwuo0hf.pdf

Accumulation of blood-circulating PD-L1-expressing M-MDSCs and monocytes/macrophages in pretreatment ovarian cancer patients is associated with soluble PD-L1

Background The objective of this prospective study was to evaluate whether soluble programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) and serum amyloid A1 (SAA1) are potential diagnostic, predictive or prognostic biomarkers in lung cancer. Methods Lung cancer patients (n=115) with advanced metastatic disease, 101 with non-small cell lung cancer, NSCLC (77 EGFR wild-type NSCLC patients on chemotherapy, 15 EGFR mutation positive adenocarcinoma patients, 9 patients with mPD-L1 Expression ≥50% NSCLC - responders to immunotherapy), and 14 patients with small cell lung cancer (SCLC) were examined. ELISA method was used to determine sPD-L1 and SAA1 concentrations in patients' plasma. Results Significantly higher blood concentrations of sPD-L1 and SAA1 were noted in lung cancer patients compared with a healthy control group. In PD-L1+ NSCLC patients, a significantly higher sPD-L1 level was noticed compared to any other lung cancer subgroup, as well as the highest average SAA1 value compared to other subgroups. Conclusions It seems that sPD-1/PD-L1 might be a potential biomarker, prognostic and/ or predictive, particularly in patients treated with immunotherapy. Serum amyloid A1 has potential to act as a good predictor of patients' survival, as well as a biomarker of a more advanced disease, with possibly good capability to predict the course of disease measured at different time points.

/pdf/soluble-spd-l1-and-serum-amyloid-a1-as-potential-biomarkers-5dmgqzssm6.pdf

Soluble sPD-L1 and Serum Amyloid A1 as Potential Biomarkers for Lung Cancer.

Background/Aim. Thymoma is the most common mediastinal tumor. The treatment procedures are based on the results from the research of retrospective studies because they are not frequent tumors. The aim of this work was to define common clinical features, therapeutic aspects, survival and recurrence free survival. Methods. This study was performed in the Clinic for Pulmonology, Clinical Centre of Serbia, Belgrade from January 1993 to December 2013. We analyzed 62 patients with histopathologically proven thymoma. The results were obtaind from medical history, physical exam, chest X-ray and/or computed tomography and operational findings or diagnostic procedure reports. Thymomas were clasiffied according to the World Health Organization classifying system, based on histopathological findings, and staged according to the Masaoka-Koga staging system. Results. There were more female (54.8%) patients. Patients were mostly in the seventh decade of life. One third (29%) of the patients were asymptomatic. Cough was the dominant symptom. Myasthenia gravis was the most common paraneoplastic syndrome (12.9%). Solitary tumor was the most common in our patients (61.3%), as well as the tumors larger than 5 cm (52.5%), and noninvasive thymomas (52.5%). The majority of patients (40%) were in the stage I of the disease. The operative approach was conducted in most of the patients (88.7%). A statistically significant difference in survival was in women, patients with solitary tumor, non-invasive thymomas, patients in the stage I of the disease, and those who were operated. The dimension of the tumor mass approached the conventional level of significance. Conclusion. In patients with thymomas, statistically significant survival rate predictors are gender, presence of solitary tumor mass, tumor invasiveness, clinical stage and surgical treatment of the disease.

/pdf/clinicopathological-retrospective-analysis-of-thymoma-in-55ry47alaa.pdf

Clinicopathological retrospective analysis of thymoma in Serbia: Single center experience

Setting: Endobronchial tuberculosis (EBTB) is a chronic, often unrecognized form of the disease with a complicated clinical course and significant airway complications.

Objective: The aim of this study was to evaluate common clinical features amongst individuals with bronchoscopic biopsy proven EBTB during a 20 year period in Serbia.

Design: An observational study of 212 patients with bronchoscopic biopsy proven EBTB between January 1993 and December 2012. Retrospective case note review was undertaken, including all clinical, microbiological and radiological evidence, at the University Hospital of Pulmonology, Belgrade.

Results: All patients were caucasian and HIV-negative, with a male to female ratio of 1.28:1. Every patient had an abnormal chest X-ray. The most common endoscopic features were oedematous hypereamic (39.2%) and nonspecific bronchitis (35.8%). Microbiological culture rate was 64.6%. Sputum culture was positive in 55.2%, bronchial washing culture positive in 36.8%, and both in 27.4%.

Conclusion: Most patients with EBTB have concurrent pulmonary lesions. Bronchoscopy is an essential diagnostic tool for EBTB. Early diagnosis and early onset of therapy is of crucial importance to prevent the development of bronchostenosis.

https://www.longdom.org/open-access/endobronchial-tuberculosis-in-serbia-over-a-20-year-period-analysis-and-review-of-current-literature-2161-1068-1000271.pdf

Endobronchial Tuberculosis in Serbia over a 20 Year Period: Analysis and Review of Current Literature

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Papers

Soluble sPD-L1 and Serum Amyloid A1 as Potential Biomarkers for Lung Cancer.

Clinicopathological retrospective analysis of thymoma in Serbia: Single center experience

Endobronchial Tuberculosis in Serbia over a 20 Year Period: Analysis and Review of Current Literature