Wang Wenhui, Chen Jiming, Wang Shibo, Sun Xinhai, Yang Jie, Yu Pengfei, Hu Guinv, Wang Jiang, Zhang Jing, Qiao Shuya, Wang Jianli, Zhang Gensheng, He Yuzhou, Feng Huajun, Cai Zhijian
Department of Orthopaedics of the Second Affiliated Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310009, China.
Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen 361023, China; Institute of Respiratory Diseases Xiamen Medical College, Xiamen 361023, China; Organiod Platform of Medical Laboratory Science, Xiamen Medical College, Xiamen 361023, China.
Cell Rep Med. 2025 Feb 18;6(2):101922. doi: 10.1016/j.xcrm.2024.101922. Epub 2025 Jan 21.
Anti-PD-1 therapy, effective in patients with various advanced tumors, still encounters the challenge of insensitivity in most patients. Here, we demonstrate that PD-L1 on tumor cell-derived extracellular vesicles (TEVs) is critical for anti-PD-1 therapy resistance. Reducing endogenous and transferring exogenous TEVs abrogates and induces anti-PD-1 therapy resistance, respectively. Notably, PD-L1 is sorted onto TEVs via the endosomal sorting complex required for transport after ubiquitination by UBE4A and gradually upregulated on TEVs with tumor progression. During progression, increased MFGE8 from tumor cells promotes self α integrin signaling activation, enabling themselves to upregulate UBE4A, thereby increasing PD-L1 on TEVs and enhancing their immunosuppressive abilities. Translationally, anti-MFGE8-neutralizing antibodies effectively downregulate UBE4A and TEV PD-L1, thereby negating anti-PD-1 therapy resistance. Furthermore, serum MFGE8 and PD-L1 EV levels of tumor patients correlate positively, and high levels of both indicate poor prognosis after anti-PD-1 therapy. Thus, MFGE8 is a promising target for overcoming resistance and predicting responsiveness to anti-PD-1 therapy.
抗PD-1疗法对各种晚期肿瘤患者有效，但在大多数患者中仍面临不敏感的挑战。在此，我们证明肿瘤细胞衍生的细胞外囊泡（TEV）上的PD-L1对抗PD-1治疗耐药性至关重要。减少内源性TEV并转移外源性TEV分别消除和诱导抗PD-1治疗耐药性。值得注意的是，PD-L1在被UBE4A泛素化后通过运输所需的内体分选复合物被分选到TEV上，并随着肿瘤进展在TEV上逐渐上调。在肿瘤进展过程中，肿瘤细胞中增加的MFGE8促进自身α整合素信号激活，使其能够上调UBE4A，从而增加TEV上的PD-L1并增强其免疫抑制能力。在转化医学方面，抗MFGE8中和抗体有效地下调UBE4A和TEV PD-L1，从而消除抗PD-1治疗耐药性。此外，肿瘤患者血清中的MFGE8和PD-L1 EV水平呈正相关，两者水平高均表明抗PD-1治疗后预后不良。因此，MFGE8是克服耐药性和预测抗PD-1治疗反应性的一个有前景的靶点。
