Characterizing soluble immune checkpoint molecules and TGF-β1,2,3 in pleural effusion of malignant pleural mesothelioma

Our plain-English summary of Characterizing soluble immune checkpoint molecules and TGF-β1,2,3 in pleural effusion of malignant pleural mesothelioma, by R. Okita, T. Senoo, Y. Mimura-Kimura, et al (Scientific Reports, 2024).

The study

• Authors: R. Okita, T. Senoo, Y. Mimura-Kimura, Y. Mimura, T. Murakami, E. Ikeda, M. Okada, H. Inokawa, K. Aoe
• Journal: Scientific Reports
• Published: 2024;14(1):15947
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The clinical impact of soluble molecules in pleural effusion (PE) is unclear in patients with malignant pleural mesothelioma (MPM). In this single-center, retrospective, observational study, we assessed soluble forms of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-1 ligand 1 (PD-L1) using enzyme-linked immunosorbent assays; three TGF-β isoforms were measured via multiplex assay in PE of patients with fibrinous pleuritis (FP) or MPM, to assess relationships between the levels of six molecules, clinicopathological characteristics, and efficacy of immune checkpoint inhibitors. Soluble forms of CTLA-4, PD-L1, PD-1, TGF-β1, TGF-β2, and TGF-β3 were variably produced in PE of FP (n = 34) and MPM (n = 79); we found significant relationships between the six molecules and clinicopathological features. Although none of the three soluble immune checkpoint molecules showed diagnostic or prognostic effects in patients with MPM, TGF-β2 level in PE is a useful differential diagnostic marker between FP and MPM. Both TGF-β1 and TGF-β3 levels are promising prognostic markers for MPM. Moreover, we found that higher baseline levels of PD-1 soluble forms predicted the response to anti-PD1 monotherapy. Our findings identify novel diagnostic, prognostic, and predictive biomarkers for anti-PD1 therapy in patients with MPM.

© 2024. The Author(s).

In plain English

This single-center, retrospective study from Japan measured six substances in the fluid around the lungs (pleural effusion). The fluid came from 113 patients: 34 with fibrinous pleuritis, a non-cancerous inflammation of the lung lining, and 79 with malignant pleural mesothelioma. The substances were three soluble immune checkpoint molecules (sCTLA-4, sPD-L1 and sPD-1) and three forms of TGF-β. The study did not measure asbestos exposure. TGF-β2 was significantly higher in mesothelioma fluid than in pleuritis fluid (p = 0.011). In mesothelioma patients, higher TGF-β1 and TGF-β3 levels were associated with poorer overall survival. Both stayed significant after accounting for sex, tumor subtype, stage, BAP1 status and CD8 T cells. The three checkpoint molecules were not significantly associated with overall survival in this cohort. Among seven patients given an anti-PD-1 drug alone, higher sPD-1 was associated with response (partial tumor shrinkage, or disease stable for over six months; p = 0.047). The authors concluded that TGF-β2 helps tell the two conditions apart, and that TGF-β1 and TGF-β3 are promising markers of outlook. They cautioned that the sPD-1 finding rests on a small sample.

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: Single-center, retrospective, observational study of stored pleural effusion samples
• Who was studied: 113 patients (34 with fibrinous pleuritis, 79 with malignant pleural mesothelioma). Pleural effusion samples were collected between February 2007 and July 2022. The study was approved by the Yamaguchi Ube Medical Center Ethics Committee, Japan. Of the mesothelioma patients, 68 were men and 11 women, with 47 epithelioid, 25 biphasic and 7 sarcomatoid tumors.
• Exposure: No asbestos exposure was studied; asbestos appears only as background in the introduction. The study measured levels of soluble CTLA-4, PD-L1 and PD-1 (by ELISA) and of TGF-β1, TGF-β2 and TGF-β3 (by multiplex assay) in pleural effusion.
• Main results:
  • TGF-β2 was significantly higher in pleural effusion of mesothelioma patients (mean 545.8 ± 858.1 pg/ml) than of fibrinous pleuritis patients (159.0 ± 69.53 pg/ml), p = 0.011.
  • In ROC analysis, a higher TGF-β2 level was a significant diagnostic parameter for mesothelioma (p = 0.0004). The other five parameters were not significant.
  • TGF-β1 in pleural effusion was higher in sarcomatoid mesothelioma (26,084 ± 20,975 pg/ml) than in epithelioid (8649 ± 8929 pg/ml, p = 0.0003) or biphasic mesothelioma (12,667 ± 6978 pg/ml, p = 0.009).
  • In Kaplan–Meier analysis of mesothelioma patients, higher TGF-β1 (p less than 0.0001) and TGF-β3 (p = 0.028) levels were associated with poorer overall survival. The other four parameters, BAP1 status and CD8 TIL status were not significantly associated with 5-year overall survival.
  • In multivariate Cox analysis of the TGF-β cohort (n = 70), both TGF-β1 and TGF-β3 remained significantly associated with 5-year overall survival, while TGF-β2 was not. In the soluble immune checkpoint cohort, none of the three molecules was significantly associated with 5-year overall survival.
  • Multivariate hazard ratio for low vs high TGF-β1: 0.415 (95% CI 0.215–0.802), p = 0.009.
  • Multivariate hazard ratio for low vs high TGF-β3: 0.405 (95% CI 0.227–0.723), p = 0.002.
  • In mesothelioma pleural effusion, sCTLA-4 and sPD-1 levels were strongly correlated (Rs 0.755, p less than 0.0001).
  • TGF-β1 in mesothelioma pleural effusion was significantly lower with BAP1-loss tumors (9218 ± 6776 pg/ml) than with BAP1-retained tumors (15,474 ± 15,944 pg/ml, p = 0.023).
  • sCTLA-4 in mesothelioma pleural effusion was lower in cases without CD8 tumor-infiltrating T cells (10.41 ± 8.390 pg/ml) than in cases with them (19.70 ± 25.35 pg/ml, p = 0.041).
  • Among 7 patients given anti-PD-1 monotherapy, higher sPD-1 was significantly associated with response (high sPD-1: 3 responders, 0 non-responders; low sPD-1: 1 responder, 3 non-responders; p = 0.047). A responder was defined as partial response or stable disease for more than 6 months. Among all 10 patients treated with immune checkpoint inhibitors, the association was not significant (p = 0.197).
• The authors' conclusion: The authors concluded that TGF-β2 in pleural effusion is a marker for telling fibrinous pleuritis and mesothelioma apart, and that TGF-β1 and TGF-β3 levels are promising prognostic biomarkers for mesothelioma. They also concluded that none of the soluble immune checkpoint molecules showed prognostic impact, while baseline sPD-1 predicted response to anti-PD-1 monotherapy.
• Limitations the authors state:
  • Small sample size compared with similar studies of common cancers, which the authors attribute to the rarity of mesothelioma.
  • The sPD-1 finding on response to anti-PD-1 therapy should be interpreted with caution because of the small sample size; the authors call for re-evaluation in more cases.
  • Only six molecules in the pleural effusion were assessed, although many other soluble factors are present.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Pleural Mesothelioma, CTLA-4, PD-L1, checkpoint inhibitors, Biomarker.

Related studies

• Tumour cell PD-L1 expression is prognostic in patients with malignant pleural effusion: the impact of C-reactive protein and immune-checkpoint inhibition — B. Ghanim, A. Rosenmayr, et al. (2020)
• V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant pleural mesothelioma — S. Muller, W. Victoria Lai, et al. (2020)
• Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in the treatment of diffuse pleural mesothelioma: a systematic review and meta-analysis — P. Sun, D. Song, et al. (2025)
• Genetic variability of immune checkpoints in asbestos-related diseases — I. Zeljkovic, K. Goricar, et al. (2026)
• Characterization of soluble PD-L1 in pleural effusions of mesothelioma patients: potential implications in the immune response and prognosis — R. Carosio, V. Fontana, et al. (2021)
• Pre-treatment soluble PD-L1 as a predictor of overall survival for immune checkpoint inhibitor therapy: a systematic review and meta-analysis — Á. Széles, T. Fazekas, et al. (2023)

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