肿瘤的发展需要通过不同的机制进行免疫逃逸。为了抵消这些影响，针对免疫检查点（ICP）的疗法的开发引起了人们的兴趣，因为它们对晚期转移性肿瘤患者产生了持久的客观反应。然而，许多肿瘤对 ICP 抑制剂没有反应，因此需要进一步研究耗竭的潜在机制。血管内皮生长因子 a (VEGFa) 是一种由肿瘤分泌的促血管生成分子，据描述可通过增加 ICP 参与肿瘤免疫耗竭，这在一定程度上证明了在患者中使用抗 VEGFa 单克隆抗体 (mAb) 贝伐单抗的合理性。然而，我们小组最近的研究表明，肿瘤可以通过分泌可溶性 CD146 (sCD146) 逃避抗 VEGFa 治疗。在这项研究中，我们发现 VEGFa 和 sCD146 共同通过增加 ICP 的表达来创建免疫抑制微环境。此外，sCD146 有利于促肿瘤 M2 型巨噬细胞并诱导促炎细胞因子的分泌。抗 sCD146 mAb 可以逆转这些效应，并与抗 VEGFa 抗体一起发挥相加效应，消除移植有黑色素瘤细胞的同基因小鼠模型中的肿瘤。因此，贝伐单抗与 mucizumab 的组合可能具有预防恶性黑色素瘤和其他 CD146 阳性肿瘤的免疫逃逸的主要治疗意义。

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 ICP, necessitating to further study the underlying mechanisms of exhaustion. Vascular Endothelial Growth Factor a (VEGFa), a pro-angiogenic molecule secreted by tumors, was described to participate to tumor immune exhaustion by increasing ICP, justifying in part the use of an anti-VEGFa monoclonal antibody (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 ICP. In addition, sCD146 favors pro-tumoral M2-type macrophages and induces the secretion of pro-inflammatory cytokines. An anti-sCD146 mAb reverses these effects and displays additive effects with 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.