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Published on: October 2, 2015
Immune Composition and Immunotherapy Outcomes of Mesothelioma With BAP1, CDKN2A, MTAP, and NF2 Alterations
Ibiayi Dagogo-Jack1, Owen Mitchell2, Elizabeth Codd3
1Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Introduction:
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 and overall survival on ipilimumab plus nivolumab was retrospectively determined according to molecular profile.
Results:
Transcriptional analysis segregated 113 mesothelioma specimens (n = 85 epithelioid, n = 28 non-epithelioid) into the following four predefined TME groups: fibrotic (n = 14), immune desert (n = 52), immune-enriched fibrotic (n = 13), and immune-enriched nonfibrotic (n = 34). The composition of the immune infiltrate was similar when tumors with BAP1 alterations were compared with BAP1 wild-type tumors. In contrast, specimens with MTAP or CDKN2A loss had global decrease in immune populations with predominance of the immune desert phenotype. There was nonsignificant 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 plus 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.
Insights
Molecular alterations in mesothelioma impact immune cell infiltration and immunotherapy response. BAP1 alterations correlate with improved survival, while NF2 and CDKN2A alterations are linked to shorter survival, highlighting the need for molecular profiling in treatment strategies.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
- Mesothelioma Research
Background:
- Current mesothelioma treatment lacks molecular integration, focusing solely on histology.
- Genomic profiles in thoracic cancers influence tumor immune microenvironment (TME) and immunotherapy effectiveness.
- Research is needed to link mesothelioma molecular alterations, immune infiltrate, and treatment outcomes.
Purpose of the Study:
- To investigate the relationship between molecular alterations (BAP1, CDKN2A, MTAP, NF2) and TME composition in mesothelioma.
- To determine if molecular profiles predict response to ipilimumab plus nivolumab immunotherapy.
- To explore novel biomarkers for mesothelioma immunotherapy.
Main Methods:
- Whole exome and transcriptomic sequencing of 113 mesothelioma specimens.
- Multiplex immunofluorescence to assess immune cell abundance and TME composition.
- Retrospective analysis of progression-free and overall survival based on molecular profiles.
Main Results:
- Transcriptional analysis identified four TME groups: fibrotic, immune desert, immune-enriched fibrotic, and immune-enriched nonfibrotic.
- MTAP or CDKN2A loss was associated with decreased immune populations and an 'immune desert' phenotype.
- BAP1 alterations correlated with improved survival, while NF2 and CDKN2A alterations correlated with shorter survival on ipilimumab/nivolumab.
Conclusions:
- Mesothelioma immune infiltrate composition differs based on 9p21 (MTAP, CDKN2A) and NF2 alterations.
- Immune infiltrate abundance does not directly predict immunotherapy outcomes.
- Future mesothelioma immunotherapy biomarker development should integrate molecular background and tumor-immune interactions.
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