Revelant Alberto, Gessoni Francesca, Montico Marcella, Dhibi Raja, Brisotto Giulia, Casarotto Mariateresa, Zanchetta Martina, Paduano Veronica, Sperti Filippo, Evangelista Chiara, Giordari Fabiana, De Re Valli, Trovò Marco, Minatel Emilio, Mascarin Maurizio, Steffan Agostino, Muraro Elena
Division of Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
Clinical Trial Office, Scientific Direction, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
Front Immunol. 2025 Apr 1;16:1534766. doi: 10.3389/fimmu.2025.1534766. eCollection 2025.
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.
恶性胸膜间皮瘤（MPM）是一种与石棉暴露相关的侵袭性肿瘤，预后较差，治疗方法包括手术、化疗和放疗。最近，免疫疗法与化疗相比能带来生存优势，但仅限于非上皮样组织学类型，这是最罕见的类型。根治性半胸放疗（RHRT）可提高MPM患者的总生存期（OS），无论其组织学类型如何，并且能够诱导免疫调节作用。在本研究中，我们旨在调查接受RHRT的MPM患者循环T淋巴细胞表型和活性的变化，以评估在这种情况下免疫疗法可能的治疗空间。为了评估RHRT的免疫调节作用，我们评估了35例MPM患者在治疗前、放疗结束时和1个月后的外周血样本。我们首先注意到，放疗前较高的淋巴细胞与单核细胞比率（LMR）水平与改善的OS相关。通过酶联免疫吸附测定（ELISA）进行的免疫监测显示，RHRT结束时血清可溶性PD-L1（sPD-L1）和干扰素-γ（IFN-γ）水平显著升高。此外，通过流式细胞术评估，放疗后T细胞（包括CD4和CD8）中PD-1细胞的百分比显著升高。所有T细胞亚群在放疗后增殖细胞的比例也显著增加。治疗后，通过细胞内染色测量，显示WT-1特异性CD4 T细胞的患者数量显著增加。通过下一代测序研究的TCR库分析显示，放疗后扩增的T细胞克隆数量增加，并且TCR克隆性与增殖性细胞毒性T淋巴细胞的百分比之间存在关联。将我们队列中获得的TCR序列与MPM患者文献队列中描述的序列进行比较，发现了共同条目，这些条目对包括WT-1在内的MPM相关抗原具有特异性。在这种情况下，LMR的预处理水平似乎具有积极的预后作用，并且RHRT似乎会诱导免疫调节作用，这是免疫疗法适用性的潜在生物标志物：即PD-1 T淋巴细胞增加、T细胞增殖、T细胞克隆扩增以及sPD-L1水平升高。这些数据表明应设计一项前瞻性研究，评估MPM患者在RHRT后进行维持免疫疗法的效果，即使是上皮样组织学类型的患者。
