MDPI: Surfaceome Profiling of Rhabdomyosarcoma Reveals B7-H3 as a Mediator of Immune Evasion (Houghton)

Rhabdomyosarcoma (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.

Abstract

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.

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Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to the understanding of its causes, and accelerate the translation of knowledge into novel therapies. Through discovery, development, and dissemination of new scientific knowledge, Greehey CCRI strives to have a national and global impact on childhood cancer. Our mission consists of three key areas — research, clinical, and education.

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Article Categories: Research Paper