Radical hemithorax radiotherapy induces an increase in circulating PD-1+ T lymphocytes and in the soluble levels of PD-L1 in malignant pleural mesothelioma patients: a possible synergy with PD-1/PD-L1 targeting treatment?

Our plain-English summary of Radical hemithorax radiotherapy induces an increase in circulating PD-1+ T lymphocytes and in the soluble levels of PD-L1 in malignant pleural mesothelioma patients: a possible synergy with PD-1/PD-L1 targeting treatment?, by A. Revelant, F. Gessoni, M. Montico, et al (Frontiers in Immunology, 2025).

The study

• Authors: A. Revelant, F. Gessoni, M. Montico, R. Dhibi, G. Brisotto, M. Casarotto, M. Zanchetta, V. Paduano, F. Sperti, C. Evangelista, F. Giordari, V. De Re, M. Trovò, E. Minatel, M. Mascarin, A. Steffan, E. Muraro
• Journal: Frontiers in Immunology
• Published: 2025;16:1534766
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant Pleural Mesothelioma (MPM) is an aggressive tumor associated with asbestos exposure, characterized by a poor prognosis, managed with surgery, chemotherapy and radiotherapy. Recently, immunotherapy gives a survival advantage compared to chemotherapy, but limited to the non-epithelioid histotype, the rarest type. Radical hemithorax radiotherapy (RHRT) improves the Overall Survival (OS) of MPM patients, irrespective of histotype, and is able to induce immunomodulatory effects. In this study we aim to investigate changes in circulating T lymphocytes phenotype and activity, in MPM patients undergoing RHRT, to evaluate a possible therapeutic space for immunotherapy in this setting. To assess immunomodulatory effects of RHRT we evaluate peripheral blood samples of 35 MPM patients collected before treatment, at the end of RT, and 1 month later. We first notice that higher Lymphocyte-to-Monocyte Ratio (LMR) levels, before RT, are associated with an improved OS. The immune monitoring performed by ELISA assays reveals a significant increase in the serum levels of soluble PD-L1 (sPD-L1) and IFN-γ at the end of RHRT. Furthermore, the percentage of PD-1+ cells, evaluated by flow cytometry, significantly raise after RHRT in T cells, both CD4+ and CD8+. Also the proportion of proliferative cells is significantly expanded after RHRT in all T cell subtypes. After treatment we observe a significant increase in the number of patients showing WT-1 specific CD4+ T cells, measured by intracellular staining. The TCR repertoire analysis, investigated by Next Generation Sequencing, reveals an increased number of expanded T-cell clones after RHRT, and an association between TCR clonality and the percentage of proliferating cytotoxic T lymphocytes. The comparison of TCR sequences obtained in our cohort with those described in a literature cohort of MPM patients, reveals common entries, specific for MPM-associated antigens including WT-1. In this setting, pre-treatment levels of LMR seem to have a positive prognostic role, and RHRT would appear to induce immunomodulating effects, potential biomarkers for immunotherapy eligibility: i.e. increased PD-1+ T lymphocytes, proliferating T cells, expanded T cell clones and augmented levels of sPD-L1. These data suggest the design of a prospective study evaluating a maintenance immunotherapy after RHRT in MPM, even in the epithelioid histotype.

Copyright © 2025 Revelant, Gessoni, Montico, Dhibi, Brisotto, Casarotto, Zanchetta, Paduano, Sperti, Evangelista, Giordari, De Re, Trovò, Minatel, Mascarin, Steffan and Muraro.

In plain English

This study looked at immune changes in the blood of people with malignant pleural mesothelioma given radical hemithorax radiotherapy (high-dose radiation to one side of the chest). It did not study asbestos exposure. The authors studied 35 patients treated between July 2020 and August 2022; serum tests covered all 35 before and at the end of treatment, while flow-cytometry T-cell typing covered 27 at those times and 10 one month later. A higher lymphocyte-to-monocyte ratio before treatment was associated with longer overall survival in one analysis (HR 0.584, 95% CI 0.374-0.911), but not significantly in a survival-curve comparison. After treatment, median blood soluble PD-L1 rose from 85.7 to 109.3 pg/mL, and the share of T cells carrying PD-1, and of dividing T cells, increased. T-cell receptor sequencing in 20 patients found more clones expanded than shrank. In samples from an earlier trial, WT-1-specific CD4+ T cells were found in 3 of 6 radically treated patients afterward, versus 0 of 6 before. The authors concluded this radiotherapy may have a combined effect with immunotherapy, but called their results not definitive.

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: Immune-monitoring study of blood samples from mesothelioma patients receiving radical hemithorax radiotherapy (MESORTIBO study), plus a retrospective analysis of samples from an earlier randomized phase III trial comparing radical with palliative radiotherapy
• Who was studied: The main cohort was 35 patients with malignant pleural mesothelioma treated July 2020 to August 2022 by a cancer center group in Aviano, Italy. Their median age was 71 (range 48-88). There were 28 men and 7 women; 28 had epithelioid and 7 non-epithelioid histology. Serum tests covered all 35 patients, T-cell immunophenotyping by flow cytometry covered 27 before and at the end of treatment and 10 one month later, and T-cell receptor sequencing covered 20. A second cohort was 43 patients from a randomized phase III trial (August 2014 to June 2017): 21 received radical hemithorax radiotherapy and 22 received palliative radiotherapy.
• Exposure: The exposure studied was radical hemithorax radiotherapy, not asbestos. It was given at 50 Gy in 25 fractions, and 6 patients received a boost to 60 Gy. All patients had earlier had surgery and cisplatin-pemetrexed chemotherapy. In the phase III cohort, the comparison arm received palliative radiotherapy.
• Main results:
  • In the 35 patients, a higher lymphocyte-to-monocyte ratio before radiotherapy was associated with better overall survival in Cox regression (HR 0.584, 95% CI 0.374-0.911; p=0.018). When patients were split at the median, the Kaplan-Meier difference was not significant (log-rank p=0.071).
  • In the 35 patients, median serum soluble PD-L1 rose from 85.7 pg/mL (IQR 79.2-104.7) before to 109.3 pg/mL (IQR 99.5-117.8) after radiotherapy (p less than 0.001).
  • In the 35 patients, median serum IFN-gamma rose from 36.8 pg/mL (IQR 30.2-43.5) to 53.7 pg/mL (IQR 36.8-87.6) at the end of radiotherapy (p less than 0.001).
  • In 27 patients, the median percentage of CD3+ T cells fell from 69.3% to 60.9% (p less than 0.001). Changes in IL-8, IL-10, Treg and Th22 cells did not remain significant after Bonferroni correction.
  • In 27 patients, the percentage of PD-1+ cells rose significantly after radiotherapy in total (CD3+), CD4+ and CD8+ T cells. The increase was still present 1 month later in the 10 patients tested then.
  • The proportion of proliferating (Ki67+) cells rose significantly after radiotherapy in all of these T-cell subtypes.
  • In the phase III cohort's radical radiotherapy arm, WT-1-specific CD4+ T-cell responses were found in 0 of 6 patients before and 3 of 6 one month after radiotherapy (p=0.046). In the palliative arm, they were found in 0 of 4 at both times. Other antigen-specific changes were not significant.
  • In 20 of the 35 patients whose T-cell receptors were sequenced, the number of significantly expanded clones after radiotherapy (344 plus or minus 274) was higher than the number of significantly contracted clones (79 plus or minus 70; p=0.0001).
  • Overall T-cell receptor clonality did not differ significantly before and after radiotherapy (mean 0.055 vs 0.063; p=0.400).
  • After radiotherapy, clonality correlated with several T-cell measures: the percentage of CD8+ cytotoxic T cells (Spearman rho 0.909, p less than 0.001), the CTL/Treg ratio (rho 0.622, p=0.030) and proliferating cytotoxic T cells (rho 0.685, p=0.017).
  • Of the most abundant T-cell receptor sequences after radiotherapy, only 25 (6.26%) were also found in 119 healthy donors. Sequences shared with a separate cohort of mesothelioma patients on immunotherapy included ones linked to tumor-associated antigens, among them WT-1.
• The authors' conclusion: The authors concluded that radical hemithorax radiotherapy could induce expansion of CD8+ T-cell clones, at least some with anti-tumor specificity. In their view, this indicates a potential synergistic effect of this radiotherapy with immunotherapy.
• Limitations the authors state:
  • Functional T-cell responses were tested against only 2 tumor-associated antigens (mesothelin and WT-1).
  • The T-cell receptor repertoire was studied only at the end of radiotherapy, although it may keep changing afterward.
  • All monitoring was done in blood; the tumor microenvironment was not examined.
  • The authors could not confirm that the expanded T-cell receptor sequences were tumor-specific.
  • Antigen-specific T-cell tests were not done on the 2020-2022 cohort because too little biological material was available.

Topics

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

Medical terms in this study, explained in our Lexicon: Hemithorax, PD-L1, Pleural Mesothelioma, PD-1/PD-L1, Asbestos Exposure, Prognosis, Chemotherapy, Immunotherapy.

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• The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study — T. Kurosaki, K. Chamoto, et al. (2023)
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