Abstract 5817: Single cell profiling of diffuse pleural mesothelioma reveals tumor cell plasticity and dynamic immune responses when exposed to platinum, pemetrexed and nivolumab

Abstract Background: Diffuse pleural mesothelioma (DPM) is an aggressive malignancy where even patients with potentially resectable disease have poor outcomes. With an evolving understanding of the role of pleurectomy/decortication (P/D) in patients with resectable disease, the need to improve upfront therapies is more urgent. In this single institution prospective pilot study of nivolumab with platinum (cisplatin/carboplatin) and pemetrexed prior to P/D (2 cycles) for patients with resectable DPM (NCT04162015), we report clinical outcomes and multimodal profiling of tumor tissue and plasma samples using single cell RNA sequencing (scRNAseq), whole exome sequencing, and gross pathological assessment. In particular, we perform in-depth exploration of DPM transcriptional heterogeneity, including tumor cell intrinsic changes and microenvironment features associated with clinical responses to ICI. Results: 22 patients received neoadjuvant chemo-immunotherapy and 19 underwent attempted P/D (2 progressed and 1 declined surgery) within 30 days of the planned resection date. In the 19 patients that went for P/D, the median OS from the start of neoadjuvant therapy was 34mos with a PFS of 14mos (median follow-up: 32mos). scRNAseq was performed on 20 resection specimens from 16 patients with available material, including three patients with matched pre/post resection specimens. We also analyzed single cell transcriptomes from five non-ICI treated DPM samples. We discover that malignant DPM cells exist on a phenotypic continuum between mesothelial-like and fibroblast-like states, defined based on transcriptional similarity to their normal counterparts. Notably, these ‘fibroblast-like’ DPM cells were present in multiple patients, including those pathologically defined as epithelioid, and were predicted to arise from the same ancestral clonal expansion based on single-cell derived copy number profiles. These cells were present in patients prior to receiving ICI, and in certain cases corresponded to samples with gross pathological features such as a spindle-like tumor cell morphology. Focusing on features defining ICI-responsive patients, we find significantly increased abundance of cytotoxic CD8 T cells, ISG+ (interferon stimulated) T cells, FOXO1+CD4+ and CXCL13+CD4+ T cells in patients with PFS greater than 12 months. Conclusions: Neoadjuvant platinum, pemetrexed, and nivolumab was reliably able to be given to patients with DPM without impacting their ability to undergo P/D. To our knowledge this is the largest cohort of DPM resection specimens analyzed by scRNA-seq and has revealed important insights into the transcriptional heterogeneity of DPM. This in depth characterization provides foundational insights needed to characterize DPM response to chemo-IO and support future biomarker development. Citation Format: Michael Offin, Matthew Zatzman, Yonit Lavin, Jennifer L. Sauter, Nataly Naser Al Deen, Nicholas Ceglia, William D. Travis, Rania G. Aly, Andreas Rimner, Annemarie Shepherd, Charles B. Simone, Mark G. Kris, Michelle S. Ginsberg, Andrew Chow, Alvaro Quintanal-Villalonga, Sohrab P. Shah, Charles M. Rudin, Valerie W. Rusch, Prasad S. Adusumilli, Marjorie G. Zauderer. Single cell profiling of diffuse pleural mesothelioma reveals tumor cell plasticity and dynamic immune responses when exposed to platinum, pemetrexed and nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5817.