Abstract
Sarcomas comprise a collection of highly heterogeneous malignancies that can be grossly grouped in the categories of sarcomas with simple or complex genomes. Since the outcome for most sarcoma patients has barely improved in the last decades, there is an urgent need for improved therapies. Immunotherapy, and especially T cell checkpoint blockade, has recently been a game-changer in cancer therapy as it produced significant and durable treatment responses in several cancer types. Currently, only a small fraction of sarcoma patients benefit from immunotherapy, supposedly due to a general lack of somatically mutated antigens (neoantigens) and spontaneous T cell immunity in most cancers. However, genomic events resulting from chromosomal instability are frequent in sarcomas with complex genomes and could drive immunity in those tumors. Improving our understanding of the mechanisms that shape the immune landscape of sarcomas will be crucial to overcoming the current challenges of sarcoma immunotherapy. This review focuses on what is currently known about the tumor microenvironment in sarcomas and how this relates to their genomic features. Moreover, we discuss novel therapeutic strategies that leverage the tumor microenvironment to increase the clinical efficacy of immunotherapy, and which could provide new avenues for the treatment of sarcomas.
Highlights
Sarcomas are a heterogeneous group of tumors arising in the bone and soft tissue.Currently, the World Health Organization recognizes over 70 distinct sarcoma subtypes, which illustrates the biological complexity of these tumors [1]
Ongoing clinical trials involving chimeric antigen receptor (CAR) T cell therapy are directed at a multitude of tumor-associated antigens regularly found in sarcomas, but predominantly in osteosarcomas and Ewing sarcomas
The composition of the tumor microenvironment (TME) in sarcomas is highly influenced by their genome
Summary
Sarcomas are a heterogeneous group of tumors arising in the bone and soft tissue. Currently, the World Health Organization recognizes over 70 distinct sarcoma subtypes, which illustrates the biological complexity of these tumors [1]. Immunotherapy, mainly through the advent of T cell checkpoint blockade therapies, has revolutionized the treatment of a number of solid cancers, ones with immunogenic features In sarcomas, it currently has limited use as only a small group of patients benefits from these therapies. Sarcomas with simple genomes often harbor a recurrent driver genomic event (e.g., translocation, mutation, or amplification), while other extensive alterations throughout the genome are not observed (Figure 1A). Chromosomal instability, on the other hand, is frequently observed in complex sarcomas and could promote immune responses via sensing of cytosolic DNA by the cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) pathway or through upregulation of ligands that can activate effector immune cells, such as NK cells [12,13]. In underlying responses to immunotherapy [15]
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