Lack of resolution of inflammation marks malignant pleural mesothelioma progression

Our plain-English summary of Lack of resolution of inflammation marks malignant pleural mesothelioma progression, by V. Gatti, M. van Welzen, A. Napoli, et al (Cancer Drug Resistance, 2026).

The study

• Authors: V. Gatti, M. van Welzen, A. Napoli, M. Dubourdeau, M. Tiberi, A. Marra, G. Giorgi, C. Gély, V. Ceci, O. Wolkenhauer, T. Mazza, S. Gupta, M. Cioce, V. Chiurchiù, V.M. Fazio
• Journal: Cancer Drug Resistance
• Published: 2026;9:24
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Aim: Malignant pleural mesothelioma (MPM) is a paradigmatic inflammation-associated cancer and a major therapeutic challenge due to its resistance to treatment. Inflammation is thought to promote both tumor progression and therapy resistance. Senescence-associated secretory phenotype (SASP)-mediated, chemotherapy-induced release of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) contributes to pemetrexed resistance in MPM cells in vitro. Methods: Pro-inflammatory mediators (PIMs) and specialized pro-resolving mediators (SPMs) were quantified in pleural exudates using liquid chromatography-tandem mass spectrometry. Single-cell RNA-sequencing datasets were analyzed to assess the distribution of SPM-producing enzymes between mesothelial and mesothelioma cells in both tumor tissue and uninvolved pleura. Least Absolute Shrinkage and Selection Operator regression (LASSO) was used to derive a composite prognostic score (CPS) from SPM-related gene expression. Results: Chemotherapy-treated patients exhibited a reduction in SPMs - including resolvins, protectins, and maresins - alongside increased prostaglandin levels. Single-cell analysis revealed differential partitioning of SPM-producing enzymes, with lower expression in mesothelioma cells compared with mesothelial cells. A five-gene CPS derived from this lipid mediator landscape independently predicted overall survival beyond conventional clinical parameters. Conclusion: Chemotherapy alters the lipid mediator composition of pleural exudates in MPM by reducing SPMs, thereby disrupting resolution pathways. This effect is consistent with an intrinsic imbalance in expression between mesothelial and mesothelioma cells. Together, these findings suggest that impaired resolution of inflammation contributes to a pro-tumorigenic, pro-inflammatory, and chemoresistant microenvironment in MPM, with potential prognostic implications.

© The Author(s) 2026.

In plain English

This laboratory study examined lipid mediators, fat-derived signalling molecules, in malignant pleural mesothelioma. Some drive inflammation; others, called pro-resolving mediators, help it settle. The authors measured 56 such molecules in pleural fluid from 19 patients: 8 who had not had chemotherapy and 11 who had received two to six cycles, mostly cisplatin plus pemetrexed. Asbestos exposure was recorded for all untreated patients but not for three of the eleven treated. No fiber type was given. Treated patients had lower levels of several pro-resolving mediators. Those with four or more cycles had higher levels of some prostaglandins. Survival did not differ significantly by treatment (P = 0.284). In public gene data, mesothelioma cells showed lower expression of enzymes that make pro-resolving mediators than non-cancerous mesothelial cells. In a public dataset, patients with higher five-gene scores had lower risk of death than those with lower scores (adjusted hazard ratio 0.61, 95% CI 0.45-0.83). The authors concluded that chemotherapy disrupts the resolution of inflammation, possibly contributing to treatment resistance. They stated that the data are observational and the cohort small.

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 laboratory study with three parts: targeted lipid measurement (lipidomics) in stored pleural fluid samples comparing chemotherapy-naive and chemotherapy-treated patients; reanalysis of published single-cell gene-expression datasets; and development of a gene-based prognostic score in the public TCGA mesothelioma dataset
• Who was studied: Pleural fluid from 19 patients with malignant pleural mesothelioma, obtained from the Mesobank research tissue bank. Eight patients were untreated and 11 had received chemotherapy. Eighteen tumors were epithelioid and one was biphasic. Table 1 lists 17 men and 2 women, aged 55 to 93 at diagnosis. Gene-expression analyses used the TCGA mesothelioma dataset (total number not stated) and published single-cell datasets of human pleura and mesothelioma (GSE243446, GSE190597). Location and dates of sample collection are not stated.
• Exposure: The comparison was chemotherapy: two to six cycles of cisplatin plus pemetrexed, with one patient given carboplatin instead of cisplatin, versus no chemotherapy. Asbestos exposure was recorded from patient history for all 8 untreated patients; three of the 11 treated patients were not recorded as asbestos-exposed. No fiber types are named.
• Main results:
  • Prostaglandins PGD2, PGE2 and PGF2-alpha were markedly higher in patients who had received four or more chemotherapy cycles
  • Patients treated with two cycles had significantly lower levels of these prostaglandins than untreated patients
  • Pro-resolving mediators RvD1, RvE1, maresin 2 and the protectins PDx and AT-PD1 were lower with longer-term chemotherapy; RvD1 was higher after two cycles. Precursor levels were not significantly changed.
  • Overall survival in the 19 patients did not differ significantly between chemotherapy-treated and untreated patients (log-rank P = 0.284)
  • Across the 19 patients, none of the pro-inflammatory mediators correlated significantly with overall survival
  • Across the 19 patients, four pro-resolving precursors (15-HEPE, 18-HEPE, 20-HDOHE, 7-HDOHE), RvE2 and protectin DX were significantly correlated with time to death
  • In single-cell data from epithelioid mesothelioma, mesothelioma cells had lower expression of several enzymes that make pro-resolving mediators than non-cancerous mesothelial cells within the tumors
  • In TCGA patients, a five-gene score (CYP3A4, ALOX15, EPHX1, GSTM4, GPX4) split patients into two groups. Those with a high score had better survival than those with a low score (P = 0.0002).
  • In TCGA patients, higher score values were linked to a 41% lower risk of death compared with lower score values (univariate hazard ratio 0.59, 95% CI 0.43-0.81)
  • In TCGA patients, the association remained after adjusting for treatment status, histological subtype and pathological stage (adjusted hazard ratio 0.61, P = 0.002, 95% CI 0.45-0.83)
  • In TCGA patients, the score's area under the curve for predicting death was 0.66 at 12 months, 0.72 at 24 months and 0.78 at 36 months. At 24 months, sensitivity was 0.588 and specificity was 0.833.
  • In TCGA patients, the low-score (higher-risk) group had a higher estimated proportion of M1 macrophages (P = 0.023). The high-score group had more plasma cells (P = 0.026).
• The authors' conclusion: The authors concluded that chemotherapy disrupts the resolution phase of inflammation in pleural mesothelioma, potentially contributing to treatment resistance and relapse. They suggested that reduced expression of enzymes making pro-resolving mediators may help sort patients by prognosis. They described these findings as preliminary and observational.
• Limitations the authors state:
  • The small cohort does not allow a causal link to be drawn between the lipid findings and treatment resistance
  • The survival comparison of 8 untreated versus 11 treated patients is underpowered, so the non-significant result should be interpreted with caution
  • Several mediators showed trends that did not reach statistical significance
  • The findings need mechanistic validation
  • Few patients remained at 36 months, limiting the robustness of later-timepoint estimates

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Pleural Mesothelioma, Chemotherapy, Pemetrexed (Alimta), Exudate, Mesothelioma, Pleura, Mesothelial Cells.

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