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. 2025 Apr;169(4):1082-1095.e4.
doi: 10.1016/j.jtcvs.2024.10.005. Epub 2024 Oct 10.

Soluble mesothelin-related peptide as a prognosticator in pleural mesothelioma patients receiving checkpoint immunotherapy

Sonali Mitra  1 , Hee-Jin Jang  1 , Allen Kuncheria  1 , Sung Wook Kang  1 , Jong Min Choi  1 , Ji Seon Shim  1 , Claire Lee  1 , Priyanka Ranchod  1 , Peter Jindra  2 , Maheshwari Ramineni  3 , Meera Patel  4 , R Taylor Ripley  5 , Shawn S Groth  5 , Shanda H Blackmon  5 , Bryan M Burt  6 , Hyun-Sung Lee  7
Affiliations

Soluble mesothelin-related peptide as a prognosticator in pleural mesothelioma patients receiving checkpoint immunotherapy

Sonali Mitra et al. J Thorac Cardiovasc Surg. 2025 Apr.

Abstract

Background: Immune checkpoint therapy (ICT) has significantly impacted the treatment of malignant pleural mesothelioma (MPM). Despite some promising results from combination therapies, nearly half of MPM patients do not benefit, underscoring the urgent need for reliable predictive biomarkers. This study assesses the prognostic value of serum soluble mesothelin-related peptide (SMRP) and PD-L1 levels in MPM patients receiving ICT.

Methods: We conducted a retrospective analysis of 125 MPM patients treated with ICT by measuring pre-ICT serum levels of SMRP and PD-L1. We also examined the correlation of these serum levels with tumor mRNA expressions of mesothelin and PD-L1. Both univariable and multivariable Cox regression analyses were used to determine independent prognosticators for overall survival (OS). A prospective ICT clinical trial and our historical cohort were included for validation.

Results: Seventy-seven patients (62%) were treated with either anti-PD-(L)1 monotherapy, and the remaining 38% received combination ICT. Higher pre-ICT SMRP levels were observed in epithelioid MPM compared to nonepithelioid MPM. Serum PD-L1 levels did not differ significantly between the different histologic groups. Univariable analysis identified durable clinical benefit, development of immune-related adverse events, and SMRP levels as significantly associated with OS. Multivariable analysis confirmed SMRP as an independent prognostic factor, with lower levels (≤1.35 nmol/L) correlating with improved OS. The association of high SMRP with worse prognosis was validated in the prospective ICT clinical trial cohort and not in our historical cohort treated without ICT.

Conclusions: SMRP is a promising serum biomarker for predicting survival in MPM patients treated with ICT and warrants prospective investigation.

Keywords: SMRP; checkpoint immunotherapy; liquid biomarker; mesothelioma; prognostic biomarker; soluble PD-L1.

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Conflict of interest statement

Conflict of Interest Statement H.S.L. reports research funding from the National Institutes of Health, the Department of Defense, the Cancer Prevention Research Institute of Texas, the Helis Medical Research Foundation, and Dan L. Duncan Comprehensive Cancer Center, and investigator-initiated preclinical and clinical research funding from Samyang Biopharm and Momotaro-Gene. B.M.B. reports research funding from the National Institute of Health and Cancer Prevention Research Institute of Texas; clinical trial funding from AstraZeneca, Novartis, and Momotaro-Gene; and serving as a consultant in non–small cell lung cancer for AstraZeneca. R.T.R. reports research support from the National Institutes of Health, the American Association of Thoracic Surgery, and the DeGregorio Family Foundation; serving on the board of directors of the Mesothelioma Applied Research Foundation (nonremunerated); and providing expert legal opinion and serving on a speakers bureau for Merck. S.H.B has received IIT funding from Natera, Steris, and Medtronic; codeveloped instruments with Scanlan and holds other patents with Mayo Clinic; and has served as a speaker for Medtronic, AstraZeneca, and Medela. S.S.G. reports proctor and speaker honoraria from Intuitive Surgical. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Figures

Figure 1.
Figure 1.. Flow Diagram of Study Cohort.
A total of 125 patients with unresectable malignant pleural mesothelioma (MPM) were treated with immune checkpoint inhibitors. The cohort included 90 patients with epithelioid MPM and 35 with non-epithelioid MPM. To identify prognostic factors to predict overall survival, we analyzed clinicopathologic factors along with soluble mesothelin-related peptide (SMRP) and soluble PD-L1 (sPD-L1) expression. An independent validation of the identified prognostic factor was conducted using our neoadjuvant checkpoint immunotherapy clinical trial cohort (NCT02592551) and a historical cohort with conventional treatment without ICT.
Figure 2.
Figure 2.. Survival Outcomes for MPM Patients Treated with Checkpoint Immunotherapy (CI=95%).
A. During a median follow-up interval of 25 months after ICT, the median overall survival was recorded at 21 months, and the median progression-free survival was 7.6 months. B. Post-ICT overall survival did not vary significantly according to MPM histology. Patients with non-epithelioid MPM tumors exhibited a tendency toward better prognosis compared to those with epithelioid MPM tumors.
Figure 3.
Figure 3.. Association of High SMRP with Unfavorable Survival in MPM Patients Treated with Checkpoint Immunotherapy.
A. Determination of cutoff values for SMRP and sPD-L1 using hazard ratios to distinguish survival differences. B. Kaplan-Meier plots showing overall survival (OS) and progression-free survival (PFS) in MPM patients receiving immune checkpoint therapy (ICT) categorized by SMRP levels (CI=95%). Higher SMRP levels are linked to poorer survival outcomes. C. Kaplan-Meier plots for OS and PFS in MPM patients treated with ICT according to sPD-L1 levels, demonstrating no significant association with survival outcomes (CI=95%).
Figure 4.
Figure 4.. SMRP levels reflect the intrinsic tumor properties.
A. Correlation between mesothelin expression and SMRP levels. There is a positive correlation between mesothelin (MSLN) mRNA expression in tumor tissues and levels of SMRP. B. Lack of correlation between tumor PD-L1 protein and mRNA expressions with soluble PD-L1 levels. No correlation is observed between tumor PD-L1 protein and mRNA expressions with soluble PD-L1 levels. C. Distinct patterns of epithelioid MPM tumors based on SMRP Levels. Unsupervised clustering of transcriptomes from 18 epithelioid MPM patients reveals distinct patterns between those with high SMRP levels (N=9) and those with low SMRP levels (N=9). Tumors with high SMRP had higher expression of E-cadherin, fibroblast activation protein (representative protein of cancer-associated fibroblast), epithelial cell adhesion molecule (EPCAM, stem cell marker), mesothelin, and cyclin D1. In contrast, tumors with low SMRP overexpressed CCL19 and CD52. D. Mesothelin Expression Correlates with SMRP Levels in epithelioid MPMs. Patients with high SMRP levels exhibit significantly higher tumor mesothelin expression in epithelioid MPMs compared to those with low SMRP. E. Consistent tumor mutational burden across SMRP levels. There is no significant difference in tumor mutational burden between patients with high SMRP levels (N=9) and those with low SMRP levels (N=9). F. Geneset enrichment analysis highlights potential therapeutic targets. Geneset enrichment analysis (GSEA) of the HALLMARK pathway shows that tumors from patients with high SMRP levels are characterized by activated unfolded protein response and TGF-beta signaling. These pathways may represent potential targets for overcoming resistance to ICT.
Figure 5.
Figure 5.. Validation of the Prognostic Role of SMRP in MPM Patients Treated with Checkpoint Immunotherapy (CI=95%).
A. In an independent cohort of MPM patients treated with neoadjuvant ICT and surgery (N=16, NCT02592551), we confirmed that high levels of SMRP (>1.35 nmol/L) are associated with a poorer prognosis in patients undergoing neoadjuvant checkpoint immunotherapy. B. The prognostic role of SMRP is distinct in MPM patients receiving ICT. Patients with high SMRP levels exhibited a tendency towards better prognosis compared to those with low SMRP in our historical cohort of MPM patients treated with conventional therapies, without ICT (N=102, PMID: 28964420).
Figure 6.
Figure 6.. Study design, results, and implications for SMRP as a prognosticator in MPM patients receiving checkpoint immunotherapy.
Central Picture
Central Picture
High SMRP links to worse survival in MPM patients receiving checkpoint immunotherapy.
See this image and copyright information in PMC

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