Genomic and T cell repertoire biomarkers associated with malignant mesothelioma survival

Our plain-English summary of Genomic and T cell repertoire biomarkers associated with malignant mesothelioma survival, by M. Nie, Z. Sun, N. Li, et al (Thoracic Cancer, 2024).

The study

• Authors: M. Nie, Z. Sun, N. Li, L. Zhou, S. Wang, M. Yuan, R. Chen, L. Zhao, J. Li, C. Bai
• Journal: Thoracic Cancer
• Published: 2024;15(19):1502-1512
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is an exceedingly rare tumor with poor prognosis due to the limited availability of effective treatment. Immunotherapy has emerged as a novel treatment approach for MM, but less than 40% of the patients benefit from it. Thus, it is necessary to identify accurate and effective biomarkers that can predict the overall survival (OS) and immunotherapy efficacy for MM.

Methods: DNA sequencing was used to identify the genomic landscape based on the data from 86 Chinese patients. T cell receptor (TCR) sequencing was used to characterize MM TCR repertoires of 28 patients between October 2016 and April 2023.

Results: Patients with TP53, NF2, or CDKN2A variants at the genomic level, as well as those exhibiting lower Shannon index (<6.637), lower evenness (<0.028), or higher clonality (≥0.194) according to baseline tumor tissue TCR indexes, demonstrated poorer OS. Furthermore, patients with TP53, CDKN2A, or CDKN2B variants and those with a lower evenness (<0.030) in baseline tumor tissue showed worse immunotherapy efficacy. The present study is the first to identify five special TCR Vβ-Jβ rearrangements associated with MM immunotherapy efficacy.

Conclusions: The present study reported the largest-scale genomic landscape and TCR repertoire of MM in Chinese patients and identified genomic and TCR biomarkers for the prognosis and immunotherapy efficacy in MM. The study results might provide new insights for prospective MM trials using specific genes, TCR indexes, and TCR clones as biomarkers and offer a reference for future antitumor drugs based on TCR-specific clones.

© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.

In plain English

This retrospective study looked at 86 Chinese patients with malignant mesothelioma (45 peritoneal, 37 pleural, four pericardial) seen in Beijing between October 2016 and April 2023. The article does not report asbestos exposure. DNA from tissue, blood or fluid samples was sequenced for all 86 patients, and T cell receptor patterns (a measure of the immune cells in the tumor) were analyzed in tumor tissue from 28. The most frequently altered genes were TP53 (25.58%), NF2 (22.09%) and BAP1 (19.77%). Among the 42 patients with survival data, those with TP53, NF2 or CDKN2A variants had significantly worse overall survival. In 23 patients, a more diverse, less clonal T cell receptor pattern was linked to better survival. Among 15 patients with assessable immunotherapy response, TP53, CDKN2A or CDKN2B variants were linked to shorter progression-free survival on immunotherapy. Among 10 immunotherapy patients with T cell receptor data, lower evenness (below 0.030) was linked to shorter progression-free survival, and certain T cell receptor types were linked to better or worse outcomes. The authors concluded that they had identified genomic and T cell receptor biomarkers for survival and immunotherapy efficacy. They noted incomplete clinical data and few immunotherapy patients.

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 patient samples using DNA sequencing and T cell receptor sequencing
• Who was studied: 86 Chinese patients with malignant mesothelioma (45 peritoneal, 37 pleural, 4 pericardial) at Peking Union Medical College Hospital, Beijing, October 2016 to April 2023. Follow-up data were available for 42 patients, of whom 17 received immunotherapy. T cell receptor sequencing was done on tumor tissue from 28 patients.
• Exposure: No asbestos or other fiber exposure is reported. The study examined gene variants (from tissue, blood, pleural effusion or ascitic fluid samples) and tumor T cell receptor patterns as predictors of survival and of response to immunotherapy.
• Main results:
  • Of the 86 patients, 45 had peritoneal mesothelioma (52.33%), 37 pleural (43.02%) and four pericardial (4.65%).
  • Most frequently altered genes among the 86 patients: TP53 25.58%, NF2 22.09%, BAP1 19.77%, CDKN2A 15.12%, CDKN2B 10.47%.
  • Among the 42 patients with survival data, those with TP53, NF2 or CDKN2A variations had significantly worse survival than those without them (p less than 0.05).
  • Among the 42 patients, overall survival for the epithelioid subtype was significantly better than for the biphasic subtype (p less than 0.01).
  • Among the 42 patients, overall survival was significantly better in the low tumor mutational burden group than in the high group (p less than 0.05).
  • Among 23 patients with T cell receptor and survival data, a Shannon index of 6.637 or more, evenness of 0.028 or more, and clonality below 0.194 were each linked to significantly better survival.
  • In an external dataset of pleural mesothelioma patients, clonality of 0.194 or more was linked to significantly worse survival than clonality below 0.194 (p less than 0.05).
  • Among 15 immunotherapy patients with assessable response, those with TP53, CDKN2A or CDKN2B variations had significantly lower immunotherapy efficacy (p less than 0.05), measured by progression-free survival.
  • Among 10 immunotherapy patients with T cell receptor data, evenness below 0.030 was linked to notably shorter progression-free survival than evenness of 0.030 or more (p less than 0.01).
  • Among immunotherapy patients, those with T cell receptor clones carrying the V4-3 gene had worse outcomes (p less than 0.05).
  • Among immunotherapy patients, those with the V4-1 and J1-6, V5-4 and J2-5, or V10-1 and J1-4 clones had better immunotherapy efficacy (p less than 0.05).
• The authors' conclusion: The authors concluded that they had described the largest-scale genomic and T cell receptor mesothelioma repertoire in China. They also concluded that they had identified genomic and T cell receptor biomarkers for survival and for response to treatment.
• Limitations the authors state:
  • Complete clinical data could not be obtained because of the long time frame and difficulties in follow-up. Patients without clinical information were included.
  • Small numbers of sarcomatoid and biphasic subtype patients limited what could be learned about those subtypes.
  • Few patients received immunotherapy and external validation cohorts were limited.

Topics

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

Medical terms in this study, explained in our Lexicon: Biomarker, Mesothelioma, Prognosis, Immunotherapy, Overall Survival, CDKN2A.

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• Integrated genomics point to immune vulnerabilities in pleural mesothelioma — A. Nastase, A. Mandal, et al. (2021)
• Comparison of genomic abnormality in malignant mesothelioma by the site of origin — M. Takeda, T. Kasai, et al. (2014)
• T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma — H. Vroman, G. Balzaretti, et al. (2020)
• miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer — K.M. Foss, C. Sima, et al. (2011)

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