PNAS:D-甘露糖通过降解PD-L1促进三阴性乳腺癌的免疫治疗和放疗

2022-03-14 MedSci原创 MedSci原创

乳腺癌是威胁女性健康的恶性肿瘤之首,三阴性乳腺癌(Triple-negative breast cancer, TNBC)约占全部乳腺癌的15%-20%,相比于其它乳腺癌亚型,TNBC临床预后最差,易

乳腺癌是威胁女性健康的恶性肿瘤之首,三阴性乳腺癌(Triple-negative breast cancer, TNBC)约占全部乳腺癌的15%-20%,相比于其它乳腺癌亚型,TNBC临床预后最差,易发生远端转移,复发风险高。然而现阶段,临床上用于治疗乳腺癌的化疗、放疗和近几年呼声较高的免疫治疗都仍然存在一定的局限性。因此,研究人员一直在探寻新的TNBC治疗药物,试图开发出更有效的治疗方案。

2022年2月22日,复旦大学基础医学院吕雷团队与同济大学徐艳萍团队和南开大学张松团队联合在PNAS上发表了题为D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1的研究成果。该研究揭示了D-甘露糖可以通过影响PD-L1的糖基化促进其降解,进而提升TNBC免疫治疗和放疗的疗效。

甘露糖是葡萄糖的同分异构体,通过葡萄糖转运蛋白进入细胞。甘露糖在细胞内由己糖激酶催化生成6-磷酸-甘露糖(M6P),M6P可以由磷酸甘露糖异构酶(PMI)催化进入糖酵解途径由或由磷酸甘露糖变位酶(PMM2)催化进入糖基化途径。2018年Nature杂志报道的一项研究,通过筛选不同己糖对肿瘤细胞株生长的影响,发现D-甘露糖可以通过抑制葡萄糖代谢而抑制肿瘤的生长(Gonzalez et al, Nature, 2018)。

受这项工作的启发,吕雷团队试图探究各种己糖对肿瘤免疫是否产生影响。通过筛选,研究人员发现高浓度的D-甘露糖能够降解TNBC细胞中的PD-L1蛋白。深入的机制研究发现,D-甘露糖处理能够促进AMPK的激活,AMPK激活后促进了PD-L1蛋白S195位点的磷酸化,而该位点的磷酸化能够削弱PD-L1蛋白的糖基化,从而导致PD-L1蛋白通过蛋白酶体降解。定位于细胞膜表面的PD-L1是一个经典的肿瘤免疫检查点分子,靶向PD-L1/PD-1的药物一直是肿瘤免疫研究的热点。通过降解PD-L1,D-甘露糖能够促进TNBC的免疫治疗。此外,PD-L1还有另外一个重要的功能:PD-L1可以在细胞质中作为RNA结合蛋白发挥作用,保护DNA损伤修复相关基因的mRNA的稳定性,从而促进肿瘤细胞的DNA损伤修复(Tu et al, Molecular Cell, 2019)。进一步的研究发现,D-甘露糖介导的PD-L1降解还可以抑制肿瘤细胞的DNA损伤修复过程,从而对TNBC的放疗产生促进作用。在小鼠TNBC模型中,口服D-甘露糖与PD-1抗体治疗联合使用显著延长了荷瘤小鼠的生存期(在联用D-甘露糖和PD-1抗体的情况下,大约40%的小鼠在接种TNBC细胞后65天仍然存活,而单独使用PD-1抗体的小鼠在41天内全部死亡),增加了瘤体中CD8+T细胞的浸润和颗粒酶B的表达。同样地,口服D-甘露糖与电离辐射联合治疗显著抑制了小鼠体内肿瘤的生长,显著提升TNBC小鼠放疗的疗效。

总结来说,该研究揭示了D-甘露糖的一种新功能—降解PD-L1蛋白,首次报道了D-甘露糖对TNBC免疫治疗和放疗的促进作用,为TNBC的临床治疗提供了新策略。

作者信息:复旦大学基础医学院2020级博士生张若男为本文的第一作者。复旦大学基础医学院吕雷研究员、同济大学生命科学与技术学院徐艳萍教授和南开大学免疫学研究所张松教授为共同通讯作者。复旦大学基础医学院为第一作者单位。该工作得到了复旦大学基础医学院雷群英教授和杨云龙研究员,以及同济大学生命科学与技术学院陈坤教授和丁德强教授的合作支持。

原文链接:https://www.pnas.org/content/119/8/e2114851119

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    2022-11-13 drwjr
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    2022-03-16 zhouqu_8
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    2022-03-16 xlysu

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