Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma

Our plain-English summary of Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma, by N.S. Patil, L. Righi, H. Koeppen, et al (Journal of Thoracic Oncology, 2018).

The study

• Authors: N.S. Patil, L. Righi, H. Koeppen, W. Zou, S. Izzo, F. Grosso, R. Libener, M. Loiacono, V. Monica, C. Buttigliero, S. Novello, P.S. Hegde, M. Papotti, M. Kowanetz, G.V. Scagliotti
• Journal: Journal of Thoracic Oncology
• Published: 2018;13(1):124-133
• Cited by: 55 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a rare, highly aggressive, and relatively chemoresistant and radioresistant malignancy with limited therapeutic options. Our objective was to investigate the prevalence of programmed death ligand 1 (PD-L1) and the characteristics of the immune environment in this disease.

Methods: A total of 99 archival tumors from advanced-stage MPM were immunohistochemically tested in parallel for PD-L1 in two different laboratories, and 87 of them were profiled for immune gene expression by NanoString analysis for 800 genes. A prior study on the same samples indicated a low mutational load with a complex mutational landscape of genetic variations more frequently associated with the p53/DNA repair and phosphoinisitide-3-kinase pathways.

Results: PD-L1 expression was found in 16% of the MPM tumor samples, either in the tumor cells or the infiltrating immune cells. Gene expression analysis suggested that MPM is an inflamed tumor type and can be classified into three different subgroups on the basis of the different expression profiles of immune-related genes, of which two groups showed varying degrees of expression of immune-related genes. Overall, these molecular findings suggest that these subgroups of MPM associated with PD-L1 positivity and expression of immune-related genes accounting for 60% of MPMs represent a candidate subtype that may respond to cancer immunotherapy.

Conclusions: These data suggest that 60% of patients with MPM characterized by either PD-L1 expression or an inflamed status are attractive candidates for cancer immunotherapeutic options.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This retrospective laboratory study examined archived tumor samples from 99 patients with advanced (stage III and IV) malignant pleural mesothelioma at two hospitals in Turin and Alessandria, Italy. All patients received platinum-based plus pemetrexed chemotherapy. The authors measured PD-L1, a protein targeted by some immunotherapy drugs, and profiled immune-related gene activity in 87 of the samples. Asbestos exposure was reported in 42 of the 79 patients for whom this information was available. PD-L1 was found in 16% of samples, more often in biphasic and sarcomatoid tumors than in epithelioid ones. Patients with PD-L1-positive tumors had shorter survival than those with PD-L1-negative tumors (10.7 vs 18.1 months). PD-L1 status did not differ significantly by asbestos exposure, age or gender. Gene patterns sorted the tumors into three groups, and about 60% showed high immune gene activity. Asbestos exposure was not distributed significantly differently across the groups. Survival differences between the groups were not statistically significant, which the authors linked to study size. The authors concluded that their data suggest about 60% of patients, those with PD-L1 expression or an inflamed status, may be candidates for immunotherapy. The study did not measure response to immunotherapy.

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: Retrospective study of archived tumor biopsy samples (PD-L1 immunohistochemistry and immune gene expression profiling)
• Who was studied: 99 biopsy samples from patients with stage III and IV malignant pleural mesothelioma at San Luigi University Hospital (Orbassano, Turin) and S. Antonio and Biagio General Hospital (Alessandria), Italy. The samples were drawn from a previous series of 123 consecutive cases. All patients were treated with platinum-based plus pemetrexed chemotherapy, with no surgery or radiation. There were 75 epithelioid, 4 sarcomatoid and 20 biphasic tumors, and 87 samples underwent gene expression analysis. Study dates are not given.
• Exposure: The study measured PD-L1 protein and immune-related gene expression in tumors. It did not study asbestos exposure as such. Asbestos exposure was recorded only as a patient characteristic, reported in 42 of 79 patients with available information (53%), and no fiber types were named.
• Main results:
  • Counting both tumor cells and immune cells, 16% of the mesothelioma samples were PD-L1 positive.
  • Of the 14 cases with PD-L1-positive tumor cells, 5 were epithelioid, 8 biphasic and 1 sarcomatoid. This differed significantly from the distribution of tumor types in the whole series of 99 (p = 0.0004).
  • There were no statistically significant differences between PD-L1-positive and PD-L1-negative cases in age, gender or asbestos exposure.
  • PD-L1 positivity was significantly correlated with smoking habit (p = 0.01).
  • PD-L1-positive cases had a worse outcome than PD-L1-negative cases: 10.7 vs 18.1 months, HR 1.69, CI 1.16 to 2.22, p less than 0.0001.
  • Gene expression analysis of 87 tumors identified three groups: Group 1 with 35 samples (40%), Group 2 with 43 (49%) and Group 3 with 9 (10%). Groups 2 and 3, about 60% of cases, showed high expression of immune-related genes.
  • PD-L1 was highly expressed in Group 3, both as RNA and by immunohistochemistry.
  • Age, sex, asbestos exposure, smoking habit and histological type were not distributed significantly differently among the three gene expression groups.
  • Group 3 showed a trend toward poorer survival, but survival differences among the three groups were not statistically significant (p = 0.37).
  • High expression of the genes CXCL10, HMMR and RRM2 was associated with worse overall survival.
• The authors' conclusion: The authors concluded that their data suggest about 60% of patients with malignant pleural mesothelioma, characterized by either PD-L1 expression or an inflamed status, are attractive candidates for cancer immunotherapy. This was presented as a suggestion; response to immunotherapy was not tested.
• Limitations the authors state:
  • The authors attributed the lack of statistically significant survival differences among the gene expression groups to the limited study size.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, PD-L1, Immunotherapy.

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