Molecular Determinants of Soft Tissue Sarcoma Immunity: Targets for Immune Intervention

Abstract

Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of view, STSs can be classified as translocation-related and those with a heavily rearranged genotype. Although only the latter display an increased mutational burden, molecular profiles suggestive of an "immune hot" tumor microenvironment are observed across STS histologies, and response to immunotherapy has been reported in both translocation-related and genetic complex STSs. These data reinforce the notion that immunity in STSs is multifaceted and influenced by both genetic and epigenetic determinants. Cumulative evidence indicates that a fine characterization of STSs at different levels is required to identify biomarkers predictive of immunotherapy response and to discover targetable pathways to switch on the immune sensitivity of "immune cold" tumors. In this review, we will summarize recent findings on the interplay between genetic landscape, molecular profiling and immunity in STSs. Immunological and molecular features will be discussed for their prognostic value in selected STS histologies. Finally, the local and systemic immunomodulatory effects of the targeted drugs imatinib and sunitinib will be discussed.

Keywords: combination therapy; epigenetics; genetic landscape; immune profiling; immunotherapy; soft tissue sarcoma; targeted therapy; tumor microenvironment.

Figure 1

Connection between genetic and immunity in sarcomas and its translational relevance. STS dichotomization in simple and complex karyotypes does not reflect a sharp demarcation of immunogenicity and in situ immune infiltration. Along the characterization of patient- and tumor-related genetic alterations, the actual availability of high-throughput technologies has allowed immune profiling across and within distinct STS histologies. These analyses have highlighted previously unaddressed associations between genetic and/or epigenetic landscapes and peculiar immune contextures. From a translational point of view, while T cell-infiltrated STSs can benefit from immunotherapies, in T cell desert STSs, treatment by targeted or epigenetic drugs should be envisaged as therapeutic strategies to create a host environment potentially amenable to immunotherapies. Created with BioRender.com.

Figure 2

Genes modulated by imatinib in FS-DFSP. Heatmaps showing the expression levels of selected genes encoding cancer testing antigens (CTAs) or epigenetic molecules determined by RNAseq analysis of FS-DFSP pre- and post-imatinib treatment.