Resistance to Immune Checkpoint Blockade in Uterine Leiomyosarcoma: What Can We Learn from Other Cancer Types?

SIMPLE SUMMARY: Immune checkpoint blockade (ICB) has emerged as a very promising therapeutic option for patients, demonstrating unprecedented, durable responses in several difficult-to-treat cancers. Despite research indicating a strong potential for ICB in uterine leiomyosarcomas (uLMSs), a clinical trial assessing response to ICB monotherapy in uLMSs showed no clinical benefit. Resistance to ICB has been studied extensively in a variety of tumor types, but the resistance mechanisms explaining the lack of response to ICB in uLMSs remain largely unexplored. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve the effectiveness of ICB and accelerate its clinical implementation. Therefore, in this review we will explore what is known about the immunosuppressive microenvironment of uLMSs, link these data to possible resistance mechanisms extrapolated from other cancer types, and discuss potential therapeutic strategies to overcome resistance. ABSTRACT: The onset of immune checkpoint blockade (ICB) therapy over the last decade has transformed the therapeutic landscape in oncology. ICB has shown unprecedented clinical activity and durable responses in a variety of difficult-to-treat cancers. However, despite these promising long-term responses, a majority of patients fail to respond to single-agent therapy, demonstrating primary or acquired resistance. Uterine leiomyosarcoma (uLMS) is a rare high-risk gynecological cancer with very limited treatment options. Despite research indicating a strong potential for ICB in uLMS, a clinical trial assessing the response to immunotherapy with single-agent nivolumab in advanced-stage uLMS showed no clinical benefit. Many mechanisms of resistance to ICB have been characterized in a variety of tumor types, and many more continue to be uncovered. However, the mechanisms of resistance to ICB in uLMS remain largely unexplored. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. Therefore, in this review we will explore what is known about the immunosuppressive microenvironment of uLMS, link these data to possible resistance mechanisms extrapolated from other cancer types, and discuss potential therapeutic strategies to overcome resistance.