Abstract 3977: Illuminating mesothelioma immune microenvironment in response to immune checkpoint inhibitors using spatial transcriptomics

Most mesothelioma patients either have primary refractory disease or develop acquired resistance to immune checkpoint inhibitors (ICIs). A more sophisticated understanding of the tissue microenvironment (TME) and intercellular communication will enable opportunities for overcoming ICI resistance. Here, we utilize the Visium 10x spatial transcriptomics (ST) technology to address this question. We conducted ST on a cohort of 12 mesothelioma patients (28 samples) treated with ICIs (Table 1). Nine patients had a response to ICIs with a median response duration of 9 months and three had primary ICI resistant disease. We show the transition from the immune infiltrated tumor in a pre-treatment sample transition to immune exclusion in the post-treatment (ICI-resistant) sample. In addition, we were able to map the immune cell sub-types in relation to cancer cells. In a responder, we identified CXCL12-CXCR4 mediated communication at the mesothelial-immune interface. We mapped a 48-gene prognostic signature to generate spatial heat maps showing specific regions within tissue with elevated poor prognosis signatures in treatment naïve samples that expanded in matched relapsed samples. We also identified remarkable heterogeneity showing pre- and post-ICI treatment samples to be transcriptionally diverse. In another patient, we assessed four samples from the primary tumor prior to treatment, two from PET-positive and two from PET-negative areas. Moreover, we complemented spatial transcriptomics with multi-region whole genome sequencing. This revealed that these sites are genomically stable but transcriptionally distinct. Further deconvolutional analysis to approximate cell composition, cell co-localization, and cell evolution/plasticity measures are underway. Together, this deep spatial investigation provides a key understanding of oncogenic communication in TME, before and after ICI therapy. Table 1. Patient No Sex Histological Subtype Treatment Pre-Treatment samples Post Treatment samples Response Response duration 1 M Sarcomatoid PD-1 5 - Yes 6 2 M Epithelioid PD-1 3 - No - 3 M Biphasic PD-1/CTLA-4 4 - Yes 87 4 F Biphasic PD-1/CTLA-4 1 - No - 5 M Epithelioid PD-1/CTLA-4 2 1 Yes 12 6 F Sarcomatoid PD-1 1 - Yes 52 7 M Epithelioid PD-1 1 1 Yes 17 8 M Sarcomatoid PD-1/CTLA-4 2 - Yes 75 9 M Epithelioid PD-1/CTLA-4 1 1 No - 10 M Biphasic PD-1 1 1 Yes 18 11 M Sarcomatoid PD-1/CTLA-4 1 1 Yes 22 12 M Epithelioid PD-1/CTLA-4 - 1 Yes 16 Citation Format: Muhammad Alamgeer, Daniel Gough, Vinvent Xue, Beena Kumar, Adrian Pick, Fathima Sharafath Yoosuf, Surein Arulananda, Jhoseph Marquez, Vinod Ganju. Illuminating mesothelioma immune microenvironment in response to immune checkpoint inhibitors using spatial transcriptomics [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 3977.