Mesothelioma location influences the tumour microenvironment and immune checkpoint therapy response in preclinical models

Our plain-English summary of Mesothelioma location influences the tumour microenvironment and immune checkpoint therapy response in preclinical models, by M.L. Orozco Morales, S.M. Lansley, W.L. Chin, et al (Scientific Reports, 2026).

The study

• Authors: M.L. Orozco Morales, S.M. Lansley, W.L. Chin, C.M. Tilsed, N. Principe, C. Leslie, B.J. Vitali, F.X. Rwandamuriye, E. de Jong, J. Kidman, R.M. Zemek, C.A. Rinaldi, T. Lassmann, A. Bosco, Y.C.G. Lee, R.A. Lake, J. Chee, W.J. Lesterhuis
• Journal: Scientific Reports
• Published: 2026;16(1)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a cancer derived from mesothelial cells, most commonly arising from the pleura or the peritoneum. Immune checkpoint therapy (ICT) has shown survival benefit for pleural mesothelioma, but little is known about the response in peritoneal mesothelioma. Most preclinical mesothelioma models involve subcutaneous cancer cell implantation, which lacks the relevant tumour microenvironment of peritoneal mesothelioma and does not resemble the clinical presentation. We therefore set out to explore the influence of location on the mesothelioma tumour microenvironment, comparing pleural, peritoneal, and subcutaneous models using identical cell line-derived syngeneic mesotheliomas. We found that the peritoneal location conferred an anti-inflammatory tumour microenvironment, characterised by low IFN, TNFα, and STAT signalling activity, low immune cell infiltration and a gene signature associated with non-response to ICT. ICT was effective in subcutaneous models, but the same cell line-derived tumours were irresponsive when inoculated intraperitoneally. Together, these findings show that peritoneal location is associated with an immune suppressive tumour microenvironment.

In plain English

This laboratory study in mice compared mesothelioma tumours grown in three body locations. The authors injected an asbestos-induced mouse mesothelioma cell line, AB1, into the chest cavity (pleural), the abdominal cavity (peritoneal) or under the skin of female BALB/c mice. After 10 days, tumours under the skin were significantly smaller than pleural and peritoneal tumours, which showed early invasion of nearby tissues. Gene-activity analysis found inflammation-related signals were highest under the skin, then pleural, and lowest in peritoneal tumours. Pleural tumours had the most CD4+ and CD8+ T cells, while peritoneal tumours had the highest share of B cells and macrophages. After treatment with two immune checkpoint antibodies (anti-CTLA-4 and anti-PD-L1), most tumours under the skin disappeared completely. Peritoneal tumours showed partial shrinkage and improved survival but no complete disappearance. Pleural tumours were not treated in this study. The authors concluded that anatomical site influences the tumour immune environment and immunotherapy response. They noted the tumours were the sarcomatoid type and that implanted mouse tumours may not fully reflect human tumours.

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: Animal experiment (preclinical mouse study) comparing implanted mesothelioma tumours in three locations, using tissue examination, gene-expression analysis, flow cytometry and an immune checkpoint therapy treatment experiment
• Who was studied: Female BALB/c mice, and for a confirmatory experiment female C57BL/6 mice, aged 8 to 12 weeks, studied at the Harry Perkins Institute of Medical Research, Western Australia. The tumour-location experiment used 8 pleural, 7 peritoneal and 5 subcutaneous BALB/c mice. The treatment experiment used 15 subcutaneous and 15 peritoneal tumour-bearing mice.
• Exposure: Mice were not exposed to asbestos directly. They were injected with asbestos-induced mouse mesothelioma cell lines: AB1 in BALB/c mice and AE17 in C57BL/6 mice, 5 × 10^5 cells per mouse. The fiber type is not stated. In the treatment experiment, mice received the immune checkpoint antibodies anti-CTLA-4 (200 µg once) and anti-PD-L1 (200 µg three times), starting on day 5.
• Main results:
  • At day 10, pleural and peritoneal tumours weighed about the same, while subcutaneous (under-the-skin) tumours were significantly smaller.
  • Pleural and peritoneal tumours both contained clusters of lymphoid immune cells. These clusters were more common in pleural tumours than in peritoneal tumours.
  • The same pattern by location was seen with the AE17 cell line in C57BL/6 mice.
  • Inflammation-related gene signals followed a graded pattern: highest in subcutaneous tumours, then pleural tumours, and lowest in peritoneal tumours.
  • Pleural tumours had the highest infiltration of CD4+ and CD8+ T cells, followed by subcutaneous tumours.
  • Peritoneal tumours had the highest percentage of B cells and macrophages.
  • Tumour cells sorted from peritoneal tumours were mainly enriched for cell-proliferation gene pathways (MYC, E2F and G2M).
  • After immune checkpoint therapy, most subcutaneous tumours regressed completely, whichever route the treatment was given by.
  • Most peritoneal tumours showed partial regression and improved survival with treatment, but none regressed completely.
• The authors' conclusion: The authors concluded that anatomical site influences the mesothelioma immune microenvironment and, as a result, the response to immunotherapy. They also concluded that the data suggest the peritoneal space gives tumours a microenvironment resistant to immune checkpoint therapy.
• Limitations the authors state:
  • Only the sarcomatoid mesothelioma subtype was used, because few epithelioid mouse models exist.
  • Implanted tumours may not fully reproduce the genetic complexity and microenvironment of human tumours.
  • Tumours were compared at the same time point rather than at the same size, so some differences may reflect tumour size.
  • The markers used could not determine the type of macrophages present in peritoneal tumours.
  • The results are currently difficult to check against human data, because clinical trials have focused on pleural mesothelioma.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelial Cells, Pleura, Peritoneum, Pleural Mesothelioma, Peritoneal Mesothelioma.

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• Efficacy of Immune Checkpoint Inhibitors in Rare Tumours: A Systematic Review — F. Petrelli, F. Consoli, et al. (2021)
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