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

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• Leiomyosarcomas (LMS) are rare soft tissue sarcomas with poorly characterized genomic and immune profiles.
• Anatomic subtypes of LMS, such as uterine (uLMS) and non-uterine (retroperitoneal, other), exhibit distinct clinical behaviors.

Purpose of the Study:

• To define the genomic and immune landscapes of LMS by anatomic subtypes.
• To compare these profiles across subtypes and with melanoma.
• To infer real-world outcomes of immune checkpoint inhibitors (ICI) in LMS.

Main Methods:

• Comprehensive DNA/RNA sequencing of 1,115 LMS samples (uLMS, retroperitoneal LMS, oLMS).
• Comparison of genomic/transcriptomic profiles across subtypes.
• Immune profiling compared to melanoma (n=1,255).
• Analysis of insurance claims data for real-world ICI outcomes.

Main Results:

• Uterine LMS (uLMS) were molecularly distinct from non-uLMS, with specific mutations (MED12 in uLMS; RB1, MAP2K4 in non-uLMS).
• Non-uLMS showed upregulated immune gene sets and higher immune cell infiltration (CD8+ T cells, B cells) compared to uLMS.
• LMS had lower immune cell abundance and T cell-inflamed scores (TIS) than melanoma, but 11% of oLMS had high TIS.
• In real-world data, 29% of LMS patients on ICI showed potential benefit (>6 months treatment).

Conclusions:

• Uterine LMS (uLMS) is a molecularly distinct entity from non-uLMS.
• uLMS are characterized by an 'immune cold' phenotype compared to non-uLMS.
• Despite similar traditional biomarkers, immune signals in some LMS suggest potential for immunotherapy, warranting further research.