Myeloid-derived suppressor cells regulate the immunosuppressive functions of PD-1(-)PD-L1(+) Bregs through PD-L1/PI3K/AKT/NF-κB axis in breast cancer.
Myeloid-derived suppressor cells regulate the immunosuppressive functions of PD-1(-)PD-L1(+) Bregs through PD-L1/PI3K/AKT/NF-κB axis in breast cancer.
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乳腺癌中髓源性抑制细胞通过 PD-L1/PI3K/AKT/NF-kappa B 轴调节 PD-1(-)PD-L1( ) Bregs 的免疫抑制功能
DOI：
10.1038/s41419-021-03745-1
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发表时间：
2021-05-09
影响因子：
9
通讯作者：
Sun Q
中科院分区：
文献类型：
--
作者：
Liu M;Wei F;Wang J;Yu W;Shen M;Liu T;Zhang D;Wang Y;Ren X;Sun Q
髓源性抑制细胞（MDSC）是一组与肿瘤免疫逃逸密切相关的异质性髓系细胞，但其调控B细胞的机制尚未阐明。我们前期的研究发现，乳腺癌来源的MDSCs可以诱导一组具有免疫抑制功能的PD-1−PD-L1+ Bcl 3。在这里，我们报道了阻断MDSC和B细胞之间的PD-1/PD-L1相互作用可以逆转PD-1−PD-L1+ BclA的免疫抑制功能。PI 3 K/AKT/NF-κB信号通路的激活是PD-1−PD-L1+ BclG发挥免疫抑制作用的必要条件。MDSC通过PD-1/PD-L1轴激活B细胞的PI 3 K/AKT/NF-κB B通路。此外，PD-1/PD-L1或PI 3 K/AKT信号传导的抑制抑制了肿瘤生长和PD-1−PD-L1+ Bcl 3的免疫抑制功能。PD-1/PD-L1和PI 3 K/AKT的双重抑制具有更好的抗肿瘤作用。最后，MDSC和PD-1−PD-L1+ Bcl 2在乳腺癌组织中共定位，PD-1−PD-L1+ Bcl 2与预后不良呈正相关。因此，MDSC教育的PD-1−PD-L1+ Bcl 2及其调节机制可能有助于免疫抑制肿瘤微环境。我们的研究提出了MDSC介导的B细胞免疫调节的新机制，这可能为肿瘤免疫治疗提供新的思路。
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that are closely related to tumor immune escape, but the mechanism by which MDSCs regulate B cells has not been elucidated. Our previous studies revealed that breast cancer-derived MDSCs could induce a group of PD-1−PD-L1+ Bregs with immunosuppressive functions. Here, we reported that blocking PD-1/PD-L1 interaction between MDSCs and B cells could reverse the immunosuppressive functions of PD-1−PD-L1+ Bregs. The activation of PI3K/AKT/NF-κB signaling pathway is essential for PD-1−PD-L1+ Bregs to exert immunosuppressive effects. MDSCs activated the PI3K/AKT/NF-κB pathway in B cells via the PD-1/PD-L1 axis. Furthermore, inhibition of PD-1/PD-L1 or PI3K/AKT signaling suppressed both tumor growth and the immunosuppressive functions of PD-1−PD-L1+ Bregs. Dual suppression of PD-1/PD-L1 and PI3K/AKT exerted better antitumor effect. Finally, MDSCs and PD-1−PD-L1+ Bregs were colocalized in breast cancer tissues and PD-1−PD-L1+ Bregs were positively correlated with poor prognosis. Thus, MDSC-educated PD-1−PD-L1+ Bregs and their regulatory mechanisms could contribute to the immunosuppressive tumor microenvironment. Our study proposes a novel mechanism for MDSC-mediated regulation of B cell immunity, which might shed new light on tumor immunotherapy.+
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影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
7.3
作者：
Fleming V;Hu X;Weber R;Nagibin V;Groth C;Altevogt P;Utikal J;Umansky V
通讯作者：
Umansky V
影响因子：
4.4
作者：
Bronte, V;Serafini, P;Zanovello, P
通讯作者：
Zanovello, P
影响因子：
5.5
作者：
Crook, Kristen R.;Jin, Mengyao;Liu, Peng
通讯作者：
Liu, Peng
影响因子：
3.7
作者：
Bergenfelz C;Larsson AM;von Stedingk K;Gruvberger-Saal S;Aaltonen K;Jansson S;Jernström H;Janols H;Wullt M;Bredberg A;Rydén L;Leandersson K
通讯作者：
Leandersson K