D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1.
D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1.
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DOI：
10.1073/pnas.2114851119
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发表时间：
2022-02-22
影响因子：
11.1
通讯作者：
Lv L
中科院分区：
文献类型：
--
作者：
Zhang R;Yang Y;Dong W;Lin M;He J;Zhang X;Tian T;Yang Y;Chen K;Lei QY;Zhang S;Xu Y;Lv L
PD-L1 是众所周知的免疫检查点分子，它通过与其受体 PD-1 结合来抑制免疫监视。细胞内 PD-L1 还可以保护多种 DNA 损伤修复相关基因的信使 RNA 免遭降解，并增强肿瘤对 DNA 损伤治疗的抵抗力。三阴性乳腺癌（TNBC）的预后最差，远处复发的风险最高，并且对免疫治疗和放射治疗表现出抵抗力。在本研究中，我们发现D-甘露糖可以促进PD-L1的降解，并显着增强TNBC的免疫治疗和放疗。由于TNBC治疗仍然是一个临床挑战，我们的研究结果提供了增强TNBC治疗效果的策略，并可能具有临床应用价值。乳腺癌是全球女性最常见的恶性肿瘤，三阴性乳腺癌（TNBC）患者预后最差，复发风险最高。 TNBC 的治疗策略是有限的。迫切需要开发新方法来增强 TNBC 治疗的疗效。先前的研究表明，D-甘露糖（一种己糖）可以增强癌症化疗并抑制自身免疫性疾病的免疫病理学。在这里，我们证明 D-甘露糖可以通过降解 PD-L1 显着促进 TNBC 治疗。具体来说，D-甘露糖可以激活 AMP 激活蛋白激酶（AMPK），使 PD-L1 在 S195 处磷酸化，从而导致 PD-L1 糖基化异常和蛋白酶体降解。 D-甘露糖介导的 PD-L1 降解促进 T 细胞激活和 T 细胞杀伤肿瘤细胞。 D-甘露糖和 PD-1 阻断疗法的组合可显着抑制 TNBC 生长并延长荷瘤小鼠的寿命。此外，D-甘露糖诱导的PD-L1降解还会导致DNA损伤修复相关基因的信使RNA不稳定，从而使乳腺癌细胞对电离辐射（IR）治疗敏感并促进小鼠TNBC的放射治疗。值得注意的是，D-甘露糖的有效水平可以通过小鼠口服轻松达到。我们的研究揭示了 D-甘露糖靶向 PD-L1 降解的机制，并提供了促进 TNBC 免疫治疗和放射治疗的方法。 D-甘露糖的这种功能可能有助于TNBC的临床治疗。
PD-L1 is well known as an immune checkpoint molecule, which suppresses immune surveillance through binding to its receptor PD-1. Intracellular PD-L1 can also protect messenger RNAs of several DNA damage repair–related genes from degradation and enhance tumor resistance to DNA-damaging therapy. Triple-negative breast cancer (TNBC) has the worst prognosis and highest risk of distant relapse in breast cancer and shows resistance to immunotherapy and radiotherapy. In this study, we found that D-mannose can promote the degradation of PD-L1 and significantly enhance immunotherapy and radiotherapy of TNBC. Since TNBC treatment is still a clinical challenge, our findings provide strategies to enhance the therapeutic efficacy of TNBC and may have clinical application. Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose–mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose–induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair–related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
50.3
作者：
Lim SO;Li CW;Xia W;Cha JH;Chan LC;Wu Y;Chang SS;Lin WC;Hsu JM;Hsu YH;Kim T;Chang WC;Hsu JL;Yamaguchi H;Ding Q;Wang Y;Yang Y;Chen CH;Sahin AA;Yu D;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
64.8
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
通讯作者：
Dawson MA
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM