Large-Scale Multiomic Analysis Identifies Anatomic Differences and Immunogenic Potential in Subtypes of Leiomyosarcoma

Abstract

Purpose: Comprehensive molecular profiling was used to define not vary by anatomic site. Non-uLMS demonstrated upregulated the genomic and immune landscapes of leiomyosarcomas (LMS) by immune-related gene sets, including IFN and inflammatory re-anatomic subtypes, which have not been completely characterized. sponse pathways, and higher immune cell infiltration, especially Experimental Design: A total of 1,115 LMS samples, catego- CD8+ T cells and B cells (>2-fold increase, P < 0.0001). LMS had rized into uterine LMS (uLMS), retroperitoneal LMS, or other lower immune cell abundance and T cell–inflamed scores (TIS) LMS (oLMS), underwent DNA/RNA sequencing (Caris Life compared with melanoma, though 11% of oLMS samples had Sciences). Genomic/transcriptomic profiles were compared high TIS scores. In a real-world cohort (n ¼ 138), 29% of patients across subtypes. Immune profiling was compared with melanoma with LMS receiving ICI were treated >6 months, indicating po(n ¼ 1,255), an immunogenic tumor. Insurance claims data were tential clinical benefit. used to infer real-world outcomes with immune checkpoint in- Conclusions: Comprehensive profiling suggested that uLMS hibitors (ICI) in LMS. represents a molecularly distinct disease from non-uLMS. Al-Results: uLMSs (n ¼ 701) were molecularly distinct from though traditional ICI response biomarkers were similar across retroperitoneal LMSs (n ¼ 166) and oLMSs (n ¼ 248). RB1 anatomic subtypes, uLMSs were immune cold compared with mutations and MAP2K4 copy-number amplification were more non-uLMS. Signals for ICI responsiveness, such as high TIS and common in non-uLMS. MED12 mutations were almost exclusive immune cell abundance, in some tumors suggest that further to uLMS. Traditional ICI response biomarkers (i.e., PD-L1) did research into immunotherapies for LMS is warranted.