Linking Immunity with Genomics in Sarcomas: Is Genomic Complexity an Immunogenic Trigger?

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.

Multimodal profiling of chordoma immunity reveals distinct immune contextures

“…In other tumour types (e.g., melanoma, carcinomas) spontaneous immune responses can often be explained by the mutation burden of a cancer where tumours with high mutation burden more often experience spontaneous anti-tumour immune responses as a consequence of high neoantigen abundance. In contrast, similar to most other sarcomas, the number of somatic, coding mutations in chordomas is generally low and stable between patients making it unlikely that distinct immune responses can be explained by the overall mutation burden of the tumours 13–15,32 . Although we only found evidence for strong clonal expansion in two T cell high chordomas, the TCR repertoire was less diverse in T cell high chordoma than T cell low chordomas, which would support that antigen recognition is a potential driver of immunity in chordomas.…”

“…Recent findings have provided evidence for the presence of conspicuous immune cell infiltration in chordomas 6,7 and, encouragingly, clinical responses of chordoma patients to checkpoint blockade immunotherapy targeting CTLA-4 and/or the PD-1/PD-L1 axis have been reported 8–12 . This is an intriguing observation as chordomas display a low mutational burden and are, instead, affected by gross chromosomal alterations 13–15 . Furthermore, PD-L1 expression is rarely encountered in sarcomas, including chordomas 16–18 .…”

The interplay between neoantigens and immune cells in sarcomas treated with checkpoint inhibition

“…However, a small number of patients in these clinical studies had a notable positive clinical outcome. This observation, coupled with the complete remissions reported in individual case reports, warrants further research to decipher the precise mechanisms of the positive ICI therapy responses in sarcomas ( 11 , 12 ), and potentially to develop predictive biomarkers for ICI and other cancer immunotherapies ( 6 , 9 , 13 , 14 ). The tumor mutational burden (TMB), conventionally used as a predictive biomarker to ICI therapy in several cancer types ( 15 ), is an obvious immunogenomic property to investigate and potentially help elucidate the mechanisms associated to a positive clinical response.…”

“…However, as we will report here and as reported in previously published studies, TMB remains inconclusive as a biomarker for ICI therapy response in sarcomas ( 11 , 16 ). Therefore, in this study we were motivated to study the interplay between multiple immunogenomic properties in addition to TMB, such as neoantigen load and infiltration of several immune-cell types into the TME ( 11 , 12 ).…”