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.

Keywords: Sarcoma; chemotherapy; clinical trials; immune resistance; immune therapy; immunogenicity.

Figure 1

Multiple steps are required to generate immune response against cancer. Inhibitory factors are noted on red and facilitating factors in green. DAMP: Damage-associated molecular patterns; PAMPs: pathogens-associated molecular patterns; MHC-I: major histocompatibility complex class I; TCR: T cell receptor. Created with BioRender.com.