Clinical and prognostic implications of the TCR repertoire in leiomyosarcoma.

Abstract

11573 Background: Leiomyosarcomas (LMS) are aggressive mesenchymal tumors sometimes classified by primary location as uterine LMS (uLMS) versus extra-uterine LMS (eLMS). In pursuit of novel therapies, study of the tumor microenvironment and the repertoire of T-Cell Receptor (TCR) sequences from infiltrating T-lymphocytes could help guide the application of immunotherapy in LMS. Herein, we explore the first ever database of TCR-sequenced LMS tumors in one of the larger LMS cohorts analyzed to date. Methods: A single-institution retrospective study was performed including 117 adult patients with pathology-confirmed LMS diagnosed between 1998 and 2022 at Northwestern Medicine. Overall survival (OS), progression free survival (PFS), and relapse free survival (RFS) were analyzed using Kaplan-Meier Curves (GraphPad Prism). DNA was extracted from 61 eLMS and 39 uLMS formalin-fixed paraffin-embedded (FFPE) blocks using Qiagen’s AllPrep DNA/RNA FFPE kit and used for TCR sequencing. Results: 117 patients who met the inclusion criteria were classified as uLMS (n=54) and eLMS (n=63). Baseline patient demographics and disease characteristics are described in the table. Median OS significantly differed between uLMS and eLMS patients (559 versus 1548 days; p=0.001). Median PFS was not statistically different between metastatic uLMS versus eLMS (142 versus 159 days; p=0.63). Median RFS was not significantly different between localized uLMS versus eLMS (283 versus 429 days; p=0.30). The number of different TCR clones amongst TCRs was significantly different between the two tumor types: uLMS demonstrated a mean of 821 clones versus 2415 clones in eLMS (p=0.005). Mean CDR3 length in uLMS tumors was 47.9 (95% CI 46.53-49.25) versus 48.45 (95% CI 46.66-50.25) in eLMS tumors (p=0.10). TRBV20 was the most common gene in uLMS cases and the second most common gene in eLMS cases. Conclusions: This study provides the first analysis of the TCR repertoire in LMS patients and the largest analysis of TCR repertoire ever reported in any sarcoma subtype. eLMS tumors contained significantly more TCR clones than uLMS tumors. CDR3 did not significantly differ between cohorts, and the TRBV20 gene was frequently identified in both LMS subtypes. Further gene expression analysis and immunohistochemistry is currently underway. As might be expected, clinical outcomes were worse for uLMS including significantly lower OS. Updated data will be presented including additional information about the TCR repertoire as well as gene expression data to contextualize these findings. Baseline patient demographics and disease characteristics. uLMS (n=54) eLMS (n=63) Median Age (range) 55 years (25-91) 58 years (23-87) Female Sex: n (%) 54 (100%) 34 (54%) Median Tumor Size (range) 11 cm (1-34) 5 cm (0.7-25) Necrosis Present: n (%) 47 (87%) 33 (52%) Positive Margins: n (%) 5 (9%) 9 (14%) Stage IV Disease: n (%) 16 (30%) 5 (8%) Adjuvant Chemotherapy: n (%) 27 (50%) 4 (6%)