(P 37) DISSECTING THE TUMOR MICROENVIRONMENT OF UTERINE LEIOMYOSARCOMAS FOR TARGETED DRUG PREDICTIONS

Objective: Uterine leiomyosarcomas (ULMS) are highly lethal, rare malignancies of the uterine myometrium. They typically affect young women and confer a dismal prognosis regardless of the stage at diagnosis. Current treatments for ULMS are limited in efficacy. The lack of effective treatment options for ULMS is in part due to the limited understanding of the pathophysiology of the disease. The overall purpose of this study is to investigate the transcriptomic landscape of ULMS to derive targeted therapies.

Methods: Fresh ULMS specimens were collected from consenting patients, which were then dissociated into single cells and underwent library preparation, followed by single cell RNA sequencing (scRNA-seq). Following read alignment, standard quality control metrics, and integration with scVI, the resulting clusters were manually annotated. Tumor cells were identified using canonical markers and inferCNV. Broad cell types were then subsetted, re-integrated and clustered to identify subtypes. Tumor cell subtype markers were then leveraged for targeted drug predictions. FFPE blocks of the same tumors were used to study the spatial transcriptomic profiles of these tumors.

Results: ScRNA-seq was performed on 15 uterine sarcoma samples from 13 patients. All patients had a variety of pre-operative chemoradiation regimens. Initial annotation uncovered a complex tumor microenvironment (TME) with multiple cell types, including lymphocytes, myeloid cells, endothelial cells, and tumor cells. The subsetted tumor cells revealed notable heterogeneity with differing transcriptomic signatures, with five overarching subtypes. The five subtypes exhibited a spectrum of differentiation states and had differing drug sensitivities.

Conclusion: We present a single-cell transcriptomic atlas of ULMS, which reveals a rich TME and marked heterogeneity. The targeted drug predictions derived from the transcriptomic signatures of these tumors uncover novel therapeutic avenues for treating ULMS.