In-depth profiling of tumor tissue derived from malignant pleural mesothelioma patients identifies potential biomarkers predicting response to immune-checkpoint inhibitor therapy

Our plain-English summary of In-depth profiling of tumor tissue derived from malignant pleural mesothelioma patients identifies potential biomarkers predicting response to immune-checkpoint inhibitor therapy, by D. Shek, B. Gao, H. Mahajan, et al (Genes & Diseases, 2024).

The study

• Authors: D. Shek, B. Gao, H. Mahajan, A. Nagrial, M.S. Carlino, F. Luciani, S.A. Read, G. Ahlenstiel
• Journal: Genes & Diseases
• Published: 2024;11(6):101189
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

In plain English

This pilot study looked at tumor tissue from four Caucasian men with metastatic malignant pleural mesothelioma treated in Sydney, Australia, with two immune-checkpoint inhibitor drugs, ipilimumab and nivolumab. Their median age was 74, and all had prior asbestos exposure. The article gives no further detail on that exposure. At three months, one patient had a complete response, one had stable disease, and two had disease progression. The authors grouped the first two as responders. Using spatial gene-expression and mutation testing, the authors reported that responders' tissue had more spots assigned to T cells (250, or 5.6%, versus 137, or 2.9%). The share of tumor spots directly surrounded by T cells did not differ significantly (P = 0.85). Non-responders showed higher expression of the HAVCR2 gene in macrophages (P = 0.041), and a PTCH1 mutation was found only in their tissue. The authors concluded that the findings give preliminary insights into possible markers of treatment response that still need validation. They named the very small number of samples and the lack of a confirmation cohort as limitations.

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: Pilot study (rapid communication) using spatial gene-expression profiling (Visium) and a cancer mutation panel on stored tumor tissue from treated patients, comparing responders with non-responders
• Who was studied: Four Caucasian men with metastatic malignant pleural mesothelioma, median age 74, all with prior asbestos exposure, enrolled in the ICEMELT study (NCT04631731), approved by the Western Sydney Local Health District ethics committee, Australia. Tissue came from diagnostic tumor biopsies (patients A1, B1, C1) and from a metastasis to the temporal lobe (patient D1).
• Exposure: All patients had prior asbestos exposure; no fiber type, job or dose is given. The exposure actually studied was treatment with ipilimumab (1 mg/kg every 6 weeks) and nivolumab (3 mg/kg every 2 weeks).
• Main results:
  • On 3-month CT scans (RECIST 1.1), patient A1 had a complete response and C1 had stable disease (the responders); B1 and D1 had disease progression (the non-responders).
  • Responders' tissues (A1 and C1) had more spatial spots assigned to T cells: 250 (5.6% of their total spots), compared with 137 (2.9% of total spots) in non-responders' tissues (B1 and D1).
  • The percentage of tumor spots directly surrounded by T cells was 3.8% for A1, 0.61% for B1, 4.75% for C1 and 6.76% for D1, with no significant difference between responders and non-responders (P = 0.85).
  • In T cell spots, 122 genes differed between groups: 70 were significantly higher in non-responders and 52 in responders.
  • Responders' T cells showed stronger enrichment of genes for lymphocyte proliferation and myeloid and B cell activation. Non-responders showed activation of pathways for extracellular matrix organization and vasculature development.
  • Checkpoint genes did not differ by response in cancer cell or T cell spots. In macrophage spots, the HAVCR2 gene (which encodes TIM-3) was significantly higher in non-responders (P = 0.041).
  • In a separate analysis of chemotherapy-treated MPM patients using the TIMER 2.0 tool (not these four patients), high HAVCR2 expression combined with more infiltrating macrophages was associated with lower overall survival.
  • A mutation in the PTCH1 gene (deletion of a GCC triplet on 9q22.32) was found only in the tumor tissue of the non-responders.
  • No pattern of copy number gain or loss related to therapy response was found. Both non-responder tissues (B1 and D1) showed copy number gain of the HLA-B gene, and no HLA-B changes were detected in A1 and C1.
  • In TIMER 2.0 data, PTCH1 mutations were significantly associated with lower infiltration of CD8+ T cells in MPM. No association was found with CD4+ T cells, B cells, NK cells or macrophages.
• The authors' conclusion: The authors concluded that this pilot analysis gives insights into tumor-based molecular signatures associated with response to ipilimumab plus nivolumab in MPM patients, and that further investigation is needed to validate these preliminary findings.
• Limitations the authors state:
  • The small number of samples is a major limitation that may compromise the external validity of the findings.
  • There was no confirmation cohort to validate the results or to account for possible confounding factors such as tissue collection site, method and FFPE preservation technique.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Biomarker, checkpoint inhibitors.

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• Response to Immune Checkpoint Inhibitor Therapy in Patients with Unresectable Recurrent Malignant Pleural Mesothelioma Shown by FDG-PET and CT — K. Kitajima, M. Maruyama, et al. (2021)
• Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress — M. Perrino, F. De Vincenzo, et al. (2023)
• Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment — Y. Yoshikawa, K. Kuribayashi, et al. (2020)
• Serum cytokines as a biomarker for immune checkpoint inhibitor toxicity in patients with pleural mesothelioma — S.J. Farooqi, Z. Zhao, et al. (2024)
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