Characterization of soluble PD-L1 in pleural effusions of mesothelioma patients: potential implications in the immune response and prognosis

Our plain-English summary of Characterization of soluble PD-L1 in pleural effusions of mesothelioma patients: potential implications in the immune response and prognosis, by R. Carosio, V. Fontana, L. Mastracci, et al (Journal of Cancer Research and Clinical Oncology, 2021).

The study

• Authors: R. Carosio, V. Fontana, L. Mastracci, P. Ferro, F. Grillo, B. Banelli, P.A. Canessa, P. Dessanti, A. Vigani, A. Morabito, U. Pfeffer, A. Poggi, S. Roncella, M.P. Pistillo
• Journal: Journal of Cancer Research and Clinical Oncology
• Published: 2021;147(2):459-468
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Programmed death-ligand 1 (PD-L1) protein plays a central role in the antitumor immune response, and appears to be a predictor of prognosis and efficacy for PD-L1 and programmed death 1 (PD-1) blockade therapy. The immunoregulatory role and prognostic impact of PD-L1 soluble form (sPD-L1) have been investigated in biological fluids of patients with different tumors. In malignant pleural mesothelioma (MPM), circulating sPD-L1 has been recently reported in patients' sera, but no data are available in pleural effusions (PE). In our study, we evaluated the baseline expression levels of sPD-L1 in PE from 84 MPM patients and correlated them with PD-L1-status in matched tumors and patients' overall survival (OS).

Methods: sPD-L1 in PE was determined by ELISA and tumor PD-L1 by immunohistochemistry. Association of sPD-L1 with OS was estimated using the Cox regression model.

Results: We observed that sPD-L1 was variably expressed in all the PE and tended to be higher (by 30%) in patients with PD-L1-positive tumors (cut-off ≥ 1% stained cells) as compared to patients with PD-L1-negative tumors (geometric mean ratio = 1.28, P value = 0.288). sPD-L1 levels were significantly higher than those of sPD-1 (P value = 0.001) regardless of the MPM histotypes and they were positively correlated (r = 0.50, P value < 0.001). Moreover, high PE sPD-L1 concentrations were associated with a trend towards increased OS (hazard ratio 0.79, 95% CL 0.62-1.01, P value = 0.062).

Conclusions: Our study documents the presence of sPD-L1 in PE of MPM patients, and suggests its possible biological and prognostic role in MPM.

In plain English

This study measured soluble PD-L1 (sPD-L1), a protein involved in immune responses, in fluid collected from around the lungs (pleural effusion) of 84 people diagnosed with malignant pleural mesothelioma in La Spezia, Italy, between 2008 and 2017. The fluid was taken before any treatment. sPD-L1 was found in every sample. Its levels were higher than those of a related protein, soluble PD-1, and the two rose together. Among 74 patients whose tumor tissue was also tested, those with PD-L1-positive tumors had sPD-L1 levels about 30% higher, but this difference was not statistically significant. Each doubling of sPD-L1 went with a death rate about 20% lower (hazard ratio 0.79, 95% confidence limits 0.62–1.01), a trend that did not reach statistical significance. By the end of follow-up, 83 of the 84 patients had died. The authors called their survival finding preliminary evidence of a possible association. They noted the small sample size and the lack of functional studies. Table 1 lists 53 patients as asbestos-exposed, but the article does not report results by asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Observational biomarker study in a cohort of patients: laboratory measurement (ELISA) of soluble PD-L1 and PD-1 in pleural fluid collected before treatment, staining of matched tumor tissue (immunohistochemistry), and survival analysis by Cox regression
• Who was studied: 84 patients diagnosed with malignant pleural mesothelioma at the Pneumology Division of Azienda Sanitaria Locale 5, La Spezia, Italy, from April 2008 to February 2017, followed until 31 December 2019. Age 72 years (range 45–98); 85.7% male; 57 epithelioid and 27 non-epithelioid (15 sarcomatoid, 9 biphasic, 3 desmoplastic) tumors
• Exposure: This was not a study of asbestos exposure. The factor examined was the level of soluble PD-L1 in pleural fluid, together with tumor PD-L1 status. Table 1 lists 53 of 84 patients (63.1%) as asbestos-exposed, 29 (34.5%) as non-exposed and 2 (2.3%) as unknown. No fiber types, jobs or doses are given.
• Main results:
  • sPD-L1 was detected in the pleural fluid of all 84 patients, ranging from 23.04 to 1139.9 pg/ml (geometric mean 130.2 pg/ml). It was slightly higher in the non-epithelioid group (geometric mean 148.0) than in the epithelioid group (122.6).
  • sPD-L1 levels were higher than soluble PD-1 levels in the whole sample (geometric mean ratio 1.34, 95% CL 1.13–1.58, P = 0.001), in the epithelioid group (1.22, 95% CL 1.00–1.48, P = 0.050) and in the non-epithelioid group (1.62, 95% CL 1.16–2.28, P = 0.007).
  • sPD-L1 and soluble PD-1 levels were positively associated. Each doubling of sPD-L1 went with about a 40% increase in sPD-1 (GMR = 1.39, 95% CL 1.23–1.57; P less than 0.001), after adjustment for age, gender, neutrophil-to-lymphocyte ratio, stage, histotype and therapy.
  • Of 74 patients with both fluid and tumor tissue tested, 19 (25.7%) had PD-L1-positive tumors (1% or more of tumor cells stained) and 55 (74.3%) were PD-L1-negative.
  • Patients with PD-L1-positive tumors had pleural fluid sPD-L1 levels about 30% higher than PD-L1-negative patients (GMR = 1.28, 95% CL 0.81–2.04, P = 0.288). The difference was not statistically significant.
  • After adjustment, each doubling of sPD-L1 in pleural fluid went with a mortality rate about 20% lower (HR 0.79; 95% CL 0.62–1.01; P = 0.062). This did not meet the study's significance threshold of P = 0.05 or less.
  • Patients with PD-L1-positive tumors had a death rate about 70% higher than PD-L1-negative patients (HR 1.73; 95% CL 0.93–3.22; P = 0.086). This was also not statistically significant.
  • At the end of the study period, 83 of 84 patients (98.8%) had died. Median survival was 13.4 months (95% CL 11.0–15.8).
  • No correlation was found between sPD-L1 levels and other clinical parameters.
• The authors' conclusion: The authors concluded that their findings gave preliminary evidence of a possible association between high sPD-L1 levels in pleural fluid at diagnosis and better overall survival. They suggested this prognostic potential may be independent of tumor PD-L1 expression, and said additional investigations are needed.
• Limitations the authors state:
  • Relatively small sample size
  • No functional studies of the biological role of sPD-L1 in pleural fluid

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: PD-L1, Pleural Effusion, Mesothelioma, Prognosis, Pleural Mesothelioma, Overall Survival, Immunohistochemistry, Hazard Ratio.

Related studies

• IFN-γ upregulates membranous and soluble PD-L1 in mesothelioma cells: potential implications for the clinical response to PD-1/PD-L1 blockade — M.P. Pistillo, R. Carosio, et al. (2020)
• Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas — C. Combaz-Lair, F. Galateau-Sallé, et al. (2016)
• The PD-L1/PD-1 pathway promotes dysfunction, but not "exhaustion", in tumor-responding T cells from pleural effusions in lung cancer patients — H. Prado-Garcia, S. Romero-Garcia, et al. (2017)
• Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma — N.S. Patil, L. Righi, et al. (2018)
• Profile of soluble factors in pleural effusions predict prognosis in mesothelioma — I.M. Dick, Y.C.G. Lee, et al. (2022)
• Programmed cell death 1 ligand 1 (PD-L1) expression is associated with poor prognosis of malignant pleural mesothelioma patients with good performance status — E. Rrapaj, L. Giacometti, et al. (2021)

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