Immune Composition and Immunotherapy Outcomes of Mesothelioma with BAP1, CDKN2A, MTAP, and NF2 Alterations.

IF 21 1区医学 Q1 ONCOLOGY

Journal of Thoracic Oncology Pub Date : 2025-06-25 DOI:10.1016/j.jtho.2025.06.018

Ibiayi Dagogo-Jack, Owen Mitchell, Elizabeth Codd, Annie Li, Dawn Mitchell, Samantha E Flynn, Nanna Sivamanoharan, Patrick Reeves, Mark Poznansky, Ivan Valiev, Artem Kosmin, Beow Y Yeap, Grace Hambelton, A John Iafrate, Jochen K Lennerz, Yin P Hung, Hedy Kindler

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引用次数: 0

Abstract

Background: First-line mesothelioma treatment paradigms prioritize histology without integrating molecular features. Findings from other thoracic cancers suggest that tumor immune microenvironment (TME) composition and immunotherapy efficacy are informed by genomic profile. Mesothelioma studies exploring the relationship between molecular alterations, immune infiltrate, and immunotherapy outcomes are needed.

Methods: Exome and transcriptomic sequencing and multiplex immunofluorescence were performed on pleural and peritoneal mesotheliomas annotated for BAP1, CDKN2A, MTAP, and NF2 (merlin) status to infer immune cell abundance and TME composition. Progression-free survival (PFS) and overall survival (OS) on ipilimumab + nivolumab was retrospectively determined according to molecular profile.

Results: Transcriptional analysis segregated 113 mesothelioma specimens (n=85 epithelioid, n=28 non-epithelioid) into four predefined TME groups: fibrotic (n=14), immune desert (n=52), immune-enriched fibrotic (n=13), and immune-enriched non-fibrotic (n=34). The composition of the immune infiltrate was similar when tumors with BAP1 alterations were compared to BAP1 wildtype tumors. In contrast, specimens with MTAP or CDKN2A loss had global decrease in immune populations with predominance of the immune desert phenotype. There was non-significant increase in T lymphocytes in NF2-altered tumors. Multiplex immunofluorescence similarly demonstrated increased T lymphoid infiltrate in mesotheliomas with merlin loss, including regulatory T cells. On ipilimumab + nivolumab, patients with BAP1 alterations had improved survival whereas those with NF2 and CDKN2A alterations had shorter survival.

Conclusions: Composition of the immune infiltrate may be distinct for mesotheliomas with loss of 9p21 genes (i.e., MTAP, CDKN2A) and NF2 alterations. Overall immune infiltrate abundance did not align with immunotherapy outcomes. Future immunotherapy biomarker development strategies should consider molecular background and functional characterization of mesothelioma tumor-immune interactions.

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BAP1、CDKN2A、MTAP和NF2改变的间皮瘤免疫组成和免疫治疗结果

背景：一线间皮瘤治疗模式优先考虑组织学而不整合分子特征。其他胸部肿瘤的研究结果表明，肿瘤免疫微环境（TME）组成和免疫治疗效果与基因组谱有关。间皮瘤研究需要探索分子改变、免疫浸润和免疫治疗结果之间的关系。方法：对BAP1、CDKN2A、MTAP和NF2 （merlin）状态注释的胸膜和腹膜间皮瘤进行外显子组和转录组测序和多重免疫荧光分析，以推断免疫细胞丰度和TME组成。依匹单抗+纳武单抗的无进展生存期（PFS）和总生存期（OS）根据分子谱进行回顾性测定。结果：转录分析将113例间皮瘤标本（上皮样瘤85例，非上皮样瘤28例）分为4个预先定义的TME组：纤维化（14例）、免疫荒漠（52例）、免疫富集纤维化（13例）和免疫富集非纤维化（34例）。当BAP1改变的肿瘤与BAP1野生型肿瘤比较时，免疫浸润的组成相似。相比之下，MTAP或CDKN2A缺失的标本免疫群体整体减少，以免疫荒漠表型为主。在nf2改变的肿瘤中，T淋巴细胞无显著增加。多重免疫荧光同样显示在梅林丢失的间皮瘤中T淋巴浸润增加，包括调节性T细胞。ipilimumab + nivolumab， BAP1改变的患者生存率提高，而NF2和CDKN2A改变的患者生存率较短。结论：9p21基因缺失（即MTAP、CDKN2A）和NF2改变的间皮瘤免疫浸润的组成可能是不同的。总体免疫浸润丰度与免疫治疗结果不一致。未来的免疫治疗生物标志物开发策略应考虑间皮瘤肿瘤-免疫相互作用的分子背景和功能特征。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Thoracic Oncology 医学-呼吸系统

CiteScore

36.00

自引率

3.90%

发文量

1406

审稿时长

13 days

期刊介绍： Journal of Thoracic Oncology (JTO), the official journal of the International Association for the Study of Lung Cancer,is the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies.The readship includes epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonologists, radiologists, pathologists, nuclear medicine physicians, and research scientists with a special interest in thoracic oncology.