Early trials for immune checkpoint inhibitors in sarcomas have delivered mixed results, and efforts to improve outcomes now look to combinatorial strategies with novel immunotherapeutics, including some that target macrophages. To enhance our understanding of the sarcoma immune landscape, we quantified and characterized tumor-associated macrophage infiltration and expression of the targetable macrophage-related immune checkpoint CD47/SIRPα across sarcoma types. We surveyed immunohistochemical expression of CD68, CD163, CD47, and SIRPα in tissue microarrays of 1242 sarcoma specimens (spanning 24 types). Non-translocation sarcomas, particularly undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, had significantly higher counts of both CD68+ and CD163 + macrophages than translocation-associated sarcomas. Across nearly all sarcoma types, macrophages outnumbered tumor-infiltrating lymphocytes and CD163+ (M2-like) macrophages outnumbered CD68+ (M1-like) macrophages. These findings were supported by data from The Cancer Genome Atlas, which showed a correlation between increasing macrophage contributions to immune infiltration and several measures of DNA damage. CD47 expression was bimodal, with most cases showing either 0% or >90% tumor cell staining, and the highest CD47 scores were observed in chordoma, angiosarcoma, and pleomorphic liposarcoma. SIRPα scores correlated well with CD47 expression. Given the predominance of macrophage infiltrates over tumor-infiltrating lymphocytes, the bias toward M2-like (immunosuppressive) macrophage polarization, and the generally high scores for CD47 and SIRPα, macrophagefocused immunomodulatory agents, such as CD47 or IDO-1 inhibitors, may be particularly worthwhile to pursue in sarcoma patients, alone or in combination with lymphocyte-focused agents.
In the originally published version of this article, there is a duplicated western blot panel in Figure 5D. This figure shows the co-immunoprecipitation of BRG1 and members of the polycomb repressive complex 1.1 together with HA-SS18-SSX1. The image for the BRG1 western blot was inadvertently inserted instead of the BCOR western blot. The error occurred when re-introducing original western blot images to enhance image quality for publication. The correct Figure 5D, as originally submitted to Cancer Cell, is now shown here and in the online version of the paper. The authors apologize for any confusion this error may have caused.
The heterogeneity of sarcomas with regard to molecular genesis, histology, clinical characteristics, and response to treatment makes management of these rare yet diverse neoplasms particularly challenging. This review encompasses recent developments in sarcoma diagnostics and treatment, including cytotoxic, targeted, epigenetic, and immune therapy agents. In the past year, groups internationally explored the impact of adding mandatory molecular testing to histological diagnosis, reporting some changes in diagnosis and/or management; however, the impact on outcomes could not be adequately assessed. Transcriptome sequencing techniques have brought forward new diagnostic tools for identifying fusions and/or characterizing unclassified entities. Next-generation sequencing and advanced molecular techniques were also applied to identify potential targets for directed and epigenetic therapy, where preclinical studies reported results for agents active within the receptor tyrosine kinase, mTOR, Notch, Wnt, Hedgehog, Hsp90, and MDM2 signaling networks. At the level of clinical practice, modest developments were seen for some sarcoma subtypes in conventional chemotherapy and in therapies targeting the pathways activated by various receptor tyrosine kinases. In the burgeoning field of immune therapy, sarcoma work is in its infancy; however, elaborate protocols for immune stimulation are being explored, and checkpoint blockade agents advance from preclinical models to clinical studies.
Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B, a histone demethylase and component of a non-canonical polycomb repressive complex 1 (PRC1.1), as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 binds and aberrantly activates expression of developmentally regulated genes otherwise targets of polycomb-mediated repression, which is restored upon KDM2B depletion, leading to irreversible mesenchymal differentiation. Thus, SS18-SSX1 deregulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.