Abstract
Simple SummaryRhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and there is a critical need to develop efficacious and tolerable anticancer therapies against this aggressive disease. To uncover druggable RMS-associated tumor antigens, we analyzed the cell surface protein repertoire in RMS tumor cells and normal tissue. We identified several surface proteins highly enriched in RMS, including the immune checkpoint molecule B7-H3. A further analysis using patient specimens showed that B7-H3 is overexpressed in most of RMS tumors and weakly or not detected in normal organs. Interestingly, we found that B7-H3 depletion was associated with higher immune cell killing activity against tumor cells. In line with this, high B7-H3 tumor expression was associated with lower CD8 T-cell density. Our study reveals novel RMS-associated proteins for the development of targeted therapies. In addition, we demonstrate that targeting B7-H3 function can pave the way for the design of new immunotherapies in the treatment of RMS.Novel therapeutic strategies are needed for the treatment of rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children. By using a combination of cell surface proteomics and transcriptomic profiling of RMS and normal muscle, we generated a catalog of targetable cell surface proteins enriched in RMS tumors. Among the top candidates, we identified B7-H3 as the major immunoregulatory molecule expressed by RMS tumors. By using a large cohort of tissue specimens, we demonstrated that B7-H3 is expressed in a majority of RMS tumors while not detected in normal human tissues. Through a deconvolution analysis of the RMS tumor RNA-seq data, we showed that B7-H3-rich tumors are enriched in macrophages M1, NK cells, and depleted in CD8+-T cells. Furthermore, in vitro functional assays showed that B7-H3 knockout in RMS tumor cells increases T-cell mediated cytotoxicity. Altogether, our study uncovers new potential targets for the treatment of RMS and provides the first biological insights into the role of B7-H3 in RMS biology, paving the way for the development of next-generation immunotherapies.
Highlights
In order to define a set of cell surface proteins with an extracellular domain that can serve as potential therapeutic targets in RMS, we used a combination of cell surface capture and proteomic profiling on five RMS cell lines and two normal skeletal muscle cell lines (Figure 1A)
The publicly transcriptomic dataset Genotype-Tissue Expression (GTEx) containing gene expression profiles of 54 different human tissues from 948 donors was used to determine the expression of the target candidates in normal tissues
Using combined proteomic and transcriptomic analyses of RMS tumors and normal tissue, we identified several cell surface proteins enriched in RMS and with limited expression in normal tissue, suggesting they are potential RMS target candidates for antibody-based therapies
Summary
The PAX3/7-FOXO1 fusion protein drives an oncogenic transcriptional program, including the upregulation of genes involved in invasion, proliferation, and survival [4]. Fusion-negative RMS does not harbor PAX3/7FOXO1 fusion but a variety of mutations on oncogenes, including RAS, PIK3CA, FGFR4, and TP53 [5]. The current chemotherapy regimens consist of combinations of Vincristine, Dactinomycin, and Cyclophosphamide and have shown to improve the survival rates by 60–90% in patients with localized disease [6,7,8]. Long-term effects and life-threatening complications often occur in the lifetime of RMS survivors [9,10]. This underscores the need for effective and more tolerable therapies for the treatment of RMS
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