Targeting the Molecular and Immunologic Features of Leiomyosarcoma

SIMPLE SUMMARY: Immunotherapy has revolutionized cancer care across different cancer types. Unfortunately, leiomyosarcoma does not seem sensitive to the first-generation immune-based therapies. In this review, we present the results of trials of immunotherapy in leiomyosarcoma, emphasizing differences in results between soft-tissue leiomyosarcomas and uterine leiomyosarcomas. Then, we discuss the different molecular subgroups of leiomyosarcomas and how molecular alterations may impact response to immune checkpoint blockade. Based on these molecular descriptions, we propose some future directions to improve response rate of immunotherapy in leiomyosarcoma patients, through (1) better characterization of the immune microenvironment of different leiomyosarcoma molecular subtypes, (2) combination treatments of immunotherapy with therapies targeting specific molecular alterations, (3) new generations of immune-based therapies targeting other components of the immune microenvironment (macrophages). ABSTRACT: Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies.