Immunotherapy in the Treatment of Undifferentiated Pleomorphic Sarcoma and Myxofibrosarcoma

Opinion Statement Undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) are among the most common adult soft tissue sarcoma (STS) subtypes. Due to their high genetic complexity, heterogeneity, and lack of specific genetic alterations, no consistent molecular targets for targeted therapy have been identified for UPS and MFS. Recently, immune checkpoint inhibition (ICI) has emerged as a promising treatment modality for UPS and MFS. However, the efficacy of ICI in UPS and MFS remains far lower than in other cancers such as melanoma. Strategies to increase the efficacy of ICI, including selecting patients based on putative biomarkers and combining ICI with chemotherapy, targeted therapies, and/or radiation therapy, are currently in clinical development. In this review, we first summarize the clinical characteristics of UPS and MFS, examining the tumor microenvironment (TME) and its effect on the efficacy of ICI. We then review putative biomarkers of ICI response and highlight clinical trials testing ICI in patients with UPS and MFS. Finally, we discuss other forms of immunotherapy for UPS and MFS currently under preclinical investigation. The combination of ICI plus radiation therapy appears to have benefit for patients with localized UPS and MFS. ICI should be considered for patients with advanced or unresectable UPS and MFS, especially those with potential biomarkers of response such as tertiary lymphoid structures (TLS). However, singular biomarkers such as TLS may prove inadequate to predict ICI response; more accurate prediction will likely require a panel of biomarkers including TLS, immune cell infiltration, PD-L1 expression, and other TME components.