Immunotherapy targeting the PD-1/PD-L1 receptor has achieved great success in melanoma patients. Although many studies have addressed the underlying mechanisms involved in the blockade of PD-1/PD-L1 and the consequent modulation of the immune system, the mechanisms of PD-L1 upregulation and reliable biomarkers to predict the efficacy of anti-PD-1/PD-L1 therapy remain unknown. The present study demonstrates the correlation between IGFBP2 and PD-L1, revealing a novel immune-associated tumor function of IGFBP2 in facilitating nuclear accumulation of EGFR and activation of the EGFR/STAT3/PD-L1 signaling pathway in melanoma cells. Our results also suggest that combined IGFBP2 and PD-L1 expression has the potential to predict the efficacy of anti-PD-1 treatment for malignant melanoma; because the combination of high IGFBP2 and PD-L1 expression characterizes melanoma patients with worse overall survival and is associated with a better immune ecosystem. These characteristics have been confirmed by both in vitro and in vivo data. Consequently, IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway and its function as a PD-L1 regulator might suggest novel therapeutic approach for melanoma.

中文翻译：

---

IGFBP2 通过激活恶性黑色素瘤中的 EGFR-STAT3 信号通路来调节 PD-L1 表达。


针对PD-1/PD-L1受体的免疫疗法在黑色素瘤患者中取得了巨大成功。尽管许多研究已经解决了阻断 PD-1/PD-L1 以及随后调节免疫系统所涉及的潜在机制，但 PD-L1 上调的机制和预测抗 PD-1/PD-L1 功效的可靠生物标志物PD-L1 疗法仍然未知。本研究证明了IGFBP2和PD-L1之间的相关性，揭示了IGFBP2在促进黑色素瘤细胞中EGFR核积累和EGFR/STAT3/PD-L1信号通路激活方面的一种新的免疫相关肿瘤功能。我们的结果还表明，IGFBP2 和 PD-L1 的联合表达有可能预测抗 PD-1 治疗恶性黑色素瘤的疗效；因为 IGFBP2 和 PD-L1 的高表达是黑色素瘤患者总体生存率较差的特征，并且与更好的免疫生态系统相关。这些特征已被体外和体内数据证实。因此，IGFBP2 通过激活 EGFR-STAT3 信号通路来调节 PD-L1 表达，其作为 PD-L1 调节剂的功能可能为黑色素瘤提供新的治疗方法。