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Abstract Rationale Glioblastoma multiforme (GBM) is a primary brain tumor with poor prognosis. The U.S. food and drug administration approved the use of the anti-VEGF antibody bevacizumab in recurrent GBM. However, resistance to this treatment is frequent and fails to enhance the overall survival of patients. In this study, we aimed to identify novel mechanism(s) responsible for bevacizumab-resistance in CD146-positive glioblastoma. Methods The study was performed using sera from GBM patients and human GBM cell lines in culture or xenografted in nude mice. Results We found that an increase in sCD146 concentration in sera of GBM patients after the first cycle of bevacizumab treatment was significantly associated with poor progression free survival and shorter overall survival. Accordingly, in vitro treatment of CD146-positive glioblastoma cells with bevacizumab led to a high sCD146 secretion, inducing cell invasion. These effects were mediated through integrin αvβ3 and were blocked by mucizumab, a novel humanized anti-sCD146 antibody. In vivo, the combination of bevacizumab with mucizumab impeded CD146 + glioblastoma growth and reduced tumor cell dissemination to an extent significantly higher than that observed with bevacizumab alone. Conclusion We propose sCD146 to be 1/ an early biomarker to predict and 2/ a potential target to prevent bevacizumab resistance in patients with glioblastoma.

Tumor development necessitates immune escape through different mechanisms. To counteract these effects, the development of therapies targeting immune checkpoints (ICP) has generated interest as they have produced lasting objective responses in patients with advanced metastatic tumors. However, many tumors do not respond to inhibitors of ICPs, necessitating to further study the underlying mechanisms of exhaustion. VEGFa, a proangiogenic molecule secreted by tumors, was described to participate to tumor immune exhaustion by increasing ICPs, justifying in part the use of an anti-VEGFa mAb, bevacizumab, in patients. However, recent studies from our group have demonstrated that tumors can escape anti-VEGFa therapy through the secretion of soluble CD146 (sCD146). In this study, we show that both VEGFa and sCD146 cooperate to create an immunosuppressive microenvironment by increasing the expression of ICPs. In addition, sCD146 favors protumoral M2-type macrophages and induces the secretion of proinflammatory cytokines. An anti-sCD146 mAb reverses these effects and displays additive effects with the anti-VEGFa antibody to eliminate tumors in a syngeneic murine model grafted with melanoma cells. Combining bevacizumab with mucizumab could thus be of major therapeutic interest to prevent immune escape in malignant melanoma and other CD146-positive tumors., (©2024 American Association for Cancer Research.)