Emerging mechanisms of immunotherapy resistance in sarcomas

Abstract

Sarcomas are a heterogeneous group of over 150 mesenchymal neoplasms of bone and soft tissue. Clinical prognosis remains poor in the metastatic and refractory setting, despite treatment with traditional chemotherapies. A subset of sarcoma patients can exhibit remarkable responses to novel immune therapies; however, most patients will not respond. Emerging data from genetic and transcriptomic datasets suggests that patients who are resistant to checkpoint inhibitor monotherapy may have low expression of immune-related genes, suggesting that the sarcoma was not sufficiently immunogenic to trigger or maintain an immune response to generate tumor-specific immune effector cells. In this review, we discuss the emerging data surrounding potential mechanisms of resistance, including various biomarkers explored in clinical trials of immune therapy for sarcomas. We also review future directions in clinical trials that are focused on boosting tumor immunogenicity to improve the activity of checkpoint inhibitors, as well as adoptive cellular therapy approaches to bypass deficiencies in neoantigens or antigen presentation.

Immune Cells in the Tumor Microenvironment of Soft Tissue Sarcomas

“…However, the response frequency for immunotherapy in the STSs never exceeded 30%. The PD-L1 expression is considered to be prognostically favorable in many cancers, but for STSs, its value is nonuniform [131], and in most STS subtypes, the PD-L1 index is low (10-22%) [45,132].…”

Translation of oncolytic viruses in sarcoma

“…Sarcomas are generally considered to be immunologically “cold” tumors, which contributes to the poor responses observed to immunotherapies. 9 , 10 Low mutational burden, 11 lack of PD-L1 expression on tumor cells, 12 exclusion of immune cells from the tumor niche, 13 and increased presence of immunosuppressive cell types including myeloid-derived suppressor cells (MDSCs) and M2 macrophages, 14 have been identified as factors that drive immune suppression in the sarcoma tumor microenvironment (TME) ( Figure 1 ). Correlative studies reveal immunologic features, e.g., increased tumor PD-L1 expression 15 or the presence of tertiary lymphoid structures in the TME, 13 that are more prevalent in sarcoma subtypes with higher response rates to CPI therapy, e.g., undifferentiated pleomorphic sarcoma (UPS) and alveolar soft part sarcoma (ASPS).…”

Novel PD-L1- and collagen-expressing patient-derived cell line of undifferentiated pleomorphic sarcoma (JBT19) as a model for cancer immunotherapy

“…The second promising immunotherapeutic treatment option is adoptive cellular immunotherapy (ACI), which is a personalized therapy based on ex vivo-modified/expanded immune cells, which are transferred to patients to either induce a cancer-targeted immune response (active adoptive cellular immunotherapy) 13 or to target and eliminate cancer cells directly (passive adoptive cellular immunotherapy) 14 . However, immunotherapeutic options for many STS patients are limited due to multiple mechanisms of tumor immune resistance, large heterogeneity of STSs, and poor understanding of the STS immune microenvironment 15 . UPS is one of few STS subtypes where immunotherapy showed encouraging results, namely with anti-PD-1/PD-L-1 immunotherapy 16 .…”