Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients

Our plain-English summary of Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients, by S. Cedres, G. Serna, A. Gonzalez-Medina, et al (Cancers, 2023).

The study

• Authors: S. Cedres, G. Serna, A. Gonzalez-Medina, A. Valdivia, J.D. Assaf-Pastrana, P. Iranzo, A. Callejo, N. Pardo, A. Navarro, A. Martinez-Marti, I. Priano, R. Fasani, X. Guardia, J. Gonzalo, C. Carbonell, J. Frigola, R. Amat, V. Navarro, R. Dienstmann, A. Vivancos, P. Nuciforo, E. Felip
• Journal: Cancers
• Published: 2023;15(14)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.

In plain English

This study from the Vall d'Hebron Institute of Oncology, Barcelona, compared two tumor samples from each of 10 patients with malignant pleural mesothelioma, 90% with previous asbestos exposure. The first came from diagnosis, the second from disease progression. Seven received chemotherapy between samples, sometimes with immunotherapy or other agents. Three received no systemic treatment. In the treated patients, median immune cell densities fell, for example CD3+ from 979 to 407 and CD8+ from 467 to 225 cells per square millimeter. In the untreated patients four of five cell types rose, for example CD8+ from 376 to 1605 per square millimeter, while CD20+ fell from 1007 to 277. Survival comparisons by immune cell levels gave p-values from 0.06 to 1, none below the study's 0.05 threshold. Gene analysis was possible in only three treated patients. It found 93 genes with changed activity; 51 of the 81 that decreased belonged to an immune system category. The authors concluded that the immune system tends to turn off as the disease evolves. They also stated that the number of patients was too small to draw significant conclusions.

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: Small study of paired archival tumor samples (two biopsies per patient, at diagnosis and at progression), analyzed by immunohistochemistry and DNA/RNA sequencing, with a secondary survival analysis
• Who was studied: 10 patients with malignant pleural mesothelioma (MPM) treated at Vall d'Hebron Hospital, Barcelona, Spain. Median age 62 years (range 53 to 84); 70% male; 80% smokers; 90% with previous asbestos exposure; 60% stage III; nine epithelioid and one biphasic tumor. Study dates are not given.
• Exposure: The study examined treatment between the two biopsies, not asbestos dose. Asbestos exposure was recorded only as yes or no, and no fiber types were given. Seven patients received cisplatin–pemetrexed-based chemotherapy, in some cases with an oncolytic virus, anetumab–ravtansine, bevacizumab, pembrolizumab or vinorelbine. Three received no systemic treatment between biopsies.
• Main results:
  • In the 7 patients treated between samples, median immune cell densities (cells per square millimeter) at diagnosis vs. follow-up were: CD3+ 979 vs. 407, CD8+ 467 vs. 225, FOXP3+ 25 vs. 15, CD163+ 1583 vs. 1508, CD20 793 vs. 141. PD-L1 (a combined positive score, not a density) was 2 vs. 1.
  • In the 3 patients without systemic treatment between samples, median densities (cells per square millimeter) were: CD3+ 1645 vs. 2397, CD8+ 376 vs. 1605, FOXP3+ 19 vs. 121, CD163+ 2102 vs. 2377, CD20+ 1007 vs. 277. Four of the five cell types rose and CD20+ fell. PD-L1 was 3 vs. 25.
  • Across all 10 patients, median densities (cells per square millimeter) at diagnosis vs. follow-up were: CD3+ 982 vs. 712, CD8+ 422 vs. 334, FOXP3+ 22 vs. 25, CD163+ 2086 vs. 1706, CD20+ 864 vs. 199.
  • Cell density was measured as the number of cells per square millimeter.
  • In general, PD-L1 did not change between matched samples, except in two patients.
  • Median survival for the whole cohort was 25.1 months. In first (pretreatment) samples, higher CD3 density went with 43.2 vs. 23.3 months median OS (p = 0.29), and higher CD8 with 61.4 vs. 23.3 months (p = 0.13). In second samples, low CD3 went with 32.1 vs. 11 months (p = 0.06). No survival comparison reached p less than 0.05.
  • Gene expression analysis was possible in only three patients, all treated. It found 93 differentially expressed genes. Of the 81 downregulated genes, 51 (63%) belonged to the immune system process category, compared with 3 (25%) of the 12 upregulated genes.
  • DNA sequencing in the same three patients showed almost the same mutations in both samples. The only new finding was a subclonal KMT2D mutation in the second biopsy of one patient.
• The authors' conclusion: The authors concluded that their paired-sample analysis of immune profile and genomic changes shows the immune system tends to turn off as MPM evolves. They called for larger validation cohorts.
• Limitations the authors state:
  • The number of patients was too small to draw significant conclusions.
  • Genomic analysis was completed in only three pairs of samples because the biopsies were small.
  • Because of spatial and within-tumor variation in MPM, a single biopsy may not fully characterize the tumor.
  • The long time between some pairs of samples could have affected antigen reactivity.
  • The immune cells in the second biopsy were not representative of the real changes in these cells over time.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Tumor Microenvironment, Immunotherapy, Nivolumab (Opdivo), Ipilimumab (Yervoy), Chemotherapy, Immunohistochemistry, Disease Progression.

Related studies

• Efficacy of chemotherapy for malignant pleural mesothelioma according to histology in a real-world cohort — S. Cedres, J.D. Assaf, et al. (2021)
• Protocol for Mesothelioma Observational study of Risk prediction and Generation of paired benign-meso tissue samples, Including a Nested MRI Substudy (Meso-ORIGINS) — M.D.J. Neilly, A. MacPherson, et al. (2026)
• Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients — S. Cedrés, S. Ponce-Aix, et al. (2020)
• Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy — S. Cedres, A. Valdivia, et al. (2023)
• Patterns of inflammation, cell proliferation, and related gene expression in lung after inhalation of chrysotile asbestos — T.R. Quinlan, K.A. BéruBé, et al. (1995)
• Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors — S. Hendry, R. Salgado, et al. (2017)

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