Current State of Immunotherapy and Mechanisms of Immune Evasion in Ewing Sarcoma and Osteosarcoma

Abstract

We argue here that in many ways, Ewing sarcoma (EwS) is a unique tumor entity and yet, it shares many commonalities with other immunologically cold solid malignancies. From the historical perspective, EwS, osteosarcoma (OS) and other bone and soft-tissue sarcomas were the first types of tumors treated with the immunotherapy approach: more than 100 years ago American surgeon William B. Coley injected his patients with a mixture of heat-inactivated bacteria, achieving survival rates apparently higher than with surgery alone. In contrast to OS which exhibits recurrent somatic copy-number alterations, EwS possesses one of the lowest mutation rates among cancers, being driven by a single oncogenic fusion protein, most frequently EWS-FLI1. In spite these differences, both EwS and OS are allied with immune tolerance and low immunogenicity. We discuss here the potential mechanisms of immune escape in these tumors, including low representation of tumor-specific antigens, low expression levels of MHC-I antigen-presenting molecules, accumulation of immunosuppressive M2 macrophages and myeloid proinflammatory cells, and release of extracellular vesicles (EVs) which are capable of reprogramming host cells in the tumor microenvironment and systemic circulation. We also discuss the vulnerabilities of EwS and OS and potential novel strategies for their targeting.

Keywords: Ewing sarcoma; William Coley; exosome; extracellular vesicles; human endogenous retrovirus; immunosuppression; immunotherapy; osteosarcoma; retrotransposon; tumor microenvironment.

Figure 2

Immunosuppressive tumor environment and immune evasion mechanisms in EwS and OS. Oncogenic drivers and epigenetic changes in EwS, OS and other cancers activate proinflammatory pathways and increase secretion of cytokines, chemokines, growth factors and EVs. Proinflammatory microenvironment attracts resident tissue macrophages and blood-circulating monocytes, while skewing their differentiation and promoting accumulation of M2 macrophages and immature myeloid cells with tolerogenic properties. Together with cancer-associated fibroblasts (CAFs), these cells (TAMs/M2 and MDSCs) constitute a majority in the TME. They fail to efficiently activate T cells and, instead, may induce T cell anergy and exhaustion. Additional contributing mechanisms may include re-expression of retroelements (LINEs and SINEs) and endogenous retroviruses including HERV-K in tumor cells. Dissemination of these virus-like RNAs in tumor EVs and their potential uptake by immune cells and CAFs may induce innate immune responses in these cells, leading to chronic inflammation. Tumor EVs bearing TSAs and pre-formed TSA-MHC complexes may also function as a decoy to divert antitumor immunity from cancer cells, especially when taken up by bystander host cells.

Figure 1

The 100-year-old battlefield between immunotherapy and radiotherapy in treating patients with bone and soft-tissues sarcomas. Milestones and major events are documented in a chronological order.