Surfaceome Profiling of Rhabdomyosarcoma Reveals B7-H3 as Mediator of Immune-Evasion
Roxane Lavoie, M.S.1, Patricio Gargollo, M.D.1, Yohan Kim, PhD1, Emilie Baer, B.S.1, Doris A. Phelps, Ph.D.2, Cristine M. Charlesworth, Ph.D.1, Benjamin J. Madden, PhD1, Liguo Wang, PhD1, Peter J. Houghton, Ph.D.2, Cheville John, M.D.1, Haidong Dong, M.D./Ph.D1, Candace Granberg, M.D.1, Lucien Fabrice, Ph.D.1.
1Mayo Clinic, Rochester, MN, USA, 2Greehey Children's Cancer Research Institute, San Antonio, TX, USA.
BACKGROUND: Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma, with nearly 20% of patients presenting with locally aggressive and/or metastatic disease. RMS is classified into two molecular subtypes based on the expression of the fusion gene PAX3/7 FOXO1. Current chemotherapy regimens consist of combination of Vincristine, Dactinomycin and Cyclophosphamide, and long-term effects and life-threatening complications often occur in the lifetime of RMS survivors.
METHODS: 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 transcripomic profiling of RMS and normal muscle, we generated a catalogue of targetable cell-surface proteins enriched in RMS tumors.
RESULTS: 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 deconvolution analysis of 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. CONCLUSIONS: Altogether, our study uncovers new potential targets for the treatment of RMS and provides the first biological insights on the role of B7-H3 in RMS biology, paving the way for the development of next-generation immunotherapies.
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