Regional immunosuppression and associated systemic markers in focally relapsed sarcomatoid mesothelioma: case report

Our plain-English summary of Regional immunosuppression and associated systemic markers in focally relapsed sarcomatoid mesothelioma: case report, by H. Ollila, P. Kulkarni, H. Kim, et al (Journal for Immunotherapy of Cancer, 2026).

The study

• Authors: H. Ollila, P. Kulkarni, H. Kim, P. Ankola, N.K. Chintala, C. Thomas, J.L. Sauter, M. Offin, P.S. Adusumilli
• Journal: Journal for Immunotherapy of Cancer
• Published: 2026;14(4)
• Type of article: Case report
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

A 52-year-old man presented with sarcomatoid diffuse pleural mesothelioma that had relapsed at an isolated site after a complete response to dual-immune checkpoint inhibition (ICI). Targeted sequencing exhibited amplification of chromosome 9p24, encompassing JAK2, PD-L1, PD-L2, and PTPRD in the relapsed (post-ICI) tumor, compared with baseline (pre-ICI). On multiplex immunofluorescence, tumor-associated macrophages (TAMs) and CD8+ cytotoxic T lymphocytes (CTLs) made up most of the cells in baseline and relapsed tumor (59% and 47%, respectively). Baseline tumor cells expressed genes linked to extracellular matrix remodeling and epithelial-mesenchymal transition, intermixed with M2-like TAMs and tissue-resident, effector-like CTLs. Relapsed tumor cells shifted to a growth factor-driven phenotype (NT5E, NOD1, GATA2, FN1, PDCD1LG2) that is known to cause functional impairment of CTLs, which then transitioned to an exhausted state (FCRL3, CST7, GPR171, TRAT1, LAG3); exhausted CD8+ and CD4+ T cells are seen in the peripheral blood at relapse. TAMs were enriched in antigen-presentation (CD80, CD86, CXCL10), extracellular matrix-degradation (MMP9, CTSL), and CTL-suppression (ARG1, PLA2G7) pathways. Our analyses revealed that regional immunosuppression mediated by adaptive reprogramming of tumor-cell and immune-cell (TAMs, CTLs)-intrinsic changes-rather than by immune evasion or stromal exclusion-served as a mechanism of acquired resistance to dual-ICI therapy.

© Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

In plain English

This case report described one 52-year-old man with sarcomatoid diffuse pleural mesothelioma who reported no history of classical asbestos exposure or radiation. Nivolumab plus ipilimumab, two immune checkpoint drugs, produced a complete response. Ten months into treatment, a single 3.2×1.4 cm relapse appeared in the left pleura and was surgically removed. Compared with tumor taken before treatment, the relapsed tumor had gained an amplification of chromosome 9p24, including the PD-L1 and PD-L2 genes. Tumor mutational burden did not differ statistically (11 vs 9.9 mutations/megabase). Effector-type CD8+ T cells made up 27% of cells before treatment and 2% at relapse, when T cells showed an exhausted gene signature. Tumor-associated macrophages made up 25% of all cells in the baseline tumor and 15% in the relapsed tumor, and changed in function. Exhaustion markers were also higher on blood T cells at relapse. The authors concluded that their analyses suggested resistance in this patient occurred through reprogramming of tumor and immune cells, rather than antigen loss, fewer tumor-infiltrating T cells, or stromal exclusion. Twelve months after surgery the patient was under surveillance without therapy.

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: case report (one patient), comparing tumor tissue taken before immunotherapy with tumor taken at relapse, using multiplex immunofluorescence, in situ single-cell RNA analysis and genomic profiling
• Who was studied: one 52-year-old man with sarcomatoid diffuse pleural mesothelioma of the left pleura, treated at Memorial Sloan Kettering Cancer Center, New York
• Exposure: Asbestos exposure was not studied; the patient had no self-reported history of classical asbestos exposure or radiation. The treatment studied was dual immune checkpoint inhibition with nivolumab and ipilimumab.
• Main results:
  • First-line treatment with nivolumab and ipilimumab gave a complete radiographic and clinical response.
  • Ten months after treatment began, PET-CT showed relapse as a single focus (3.2×1.4 cm) in the left lower chest anterior pleura, despite ongoing treatment. The patient then underwent left pleurectomy and decortication.
  • PD-L1 was expressed by 95% of tumor cells at the original biopsy and by 100% of tumor cells at the site of relapse.
  • The relapsed tumor showed whole-arm amplification of chromosome 9p24, including JAK2, CD274 (PD-L1), PDCD1LG2 and PTPRD.
  • There were no additional mutations and no statistical differences between baseline and relapsed tumor in tumor mutational burden (11 vs 9.9 mutations/megabase) or microsatellite instability scores (2.56 vs 1.49).
  • CD8+ cytotoxic T cells and tumor-associated macrophages made up a high proportion of cells in both baseline and relapsed tumor (81% vs 72% of all cells).
  • CD8+ cytotoxic T cells with activation and effector features made up 27% of cells in baseline tumor and 2% in post-treatment tumor. The relapsed tumor instead contained CD8+ cells with an exhausted gene signature.
  • On multiplex immunofluorescence, CD8+ PD-1+ cells were significantly higher in relapsed tumor than in baseline tumor.
  • Tumor-associated macrophages made up 25% of total cells in the baseline tumor and 15% in the relapsed tumor. The 15% is the article's own figure and matches its two relapsed-tumor macrophage populations, at 11% and 4% of total cells. These macrophages expressed matrix-degrading and T-cell-suppressing genes.
  • In peripheral blood at relapse, CD8+ and CD4+ T cells showed higher expression of LAG3 (82% and 83%), TIGIT (32% and 36%) and PD-1 (17% and 39%).
  • After surgery, the patient stopped immunotherapy because of immune-related pneumonitis and encephalitis. At 12 months after resection the patient was under active surveillance without therapy.
• The authors' conclusion: The authors concluded that their analyses suggest that, in this patient, acquired resistance to dual immune checkpoint therapy occurred through adaptive reprogramming of tumor cells, CD8+ cytotoxic T cells and macrophages. They set this against well-described immune-evasion mechanisms such as antigen loss, lower T-cell infiltration or stromal exclusion. They described the relapse as showing regional immunosuppression.

Topics

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

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

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