PD-L1是HIF-1α的新型直接靶点，在缺氧条件下阻断PD-L1增强：MDSC介导的T细胞活化

PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced: MDSC-mediated T cell activation

　

程序性细胞死亡蛋白1（PD-1）是288个氨基酸的细胞表面分子，已被指定为人类免疫球蛋白超家族的膜蛋白。该蛋白在T细胞，pro-B细胞和骨髓来源的树突细胞上表达，导致这些细胞的增殖和活性的负调节[1]。程序性死亡配体1（PD-L1）是40kDa的1型跨膜蛋白，其在自身免疫疾病和病毒感染的情况下在抑制免疫系统中起主要作用[2]。在肿瘤免疫学领域，PD-L1主要在肿瘤细胞或抗原呈递细胞的细胞表面表达; PD-1 / PD-L1复合物的形成传递抑制信号，降低杀伤性T淋巴细胞的增殖和活性[3]。相反，PD-1通常在活化的淋巴细胞和骨髓衍生的树突细胞中观察到。

　

肿瘤浸润性骨髓细胞如髓源性抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAM）形成缺氧肿瘤微环境的重要组成部分。在这里，我们研究了缺氧对髓源性抑制细胞免疫检查点受体（程序性死亡[PD] -1和CTLA-4）及其各自配体（PD-1配体1 [PD-L1]，PD-L2，CD80和CD86）的影响。

 

我们证明，与来自外周淋巴器官（脾）的MDSC相比，肿瘤部位的MDSC显示出PD-L1的差异表达。

缺氧引起肿瘤小鼠脾脏MDSCs上PD-L1的快速，显著和选择性上调。这不仅限于MDSC，因为缺氧还显着增加了巨噬细胞，树突细胞和肿瘤细胞上PD-L1的表达。

此外，缺氧条件下PD-L1的上调依赖于缺氧诱导因子-1α（HIF-1α）而非HIF-2α。

染色质免疫沉淀和荧光素酶报告基因测定揭示了HIF-1α与PD-L1近端启动子中的转录活性缺氧反应元件（HRE）的直接结合。在缺氧条件下阻断PD-L1增强了MDSC介导的T细胞活化，并伴随着MDSCs IL-6和IL-10的下调。

最后，在缺氧条件下中和抗IL-10的抗体显着消除了MDSC的抑制活性。

因此，同时阻断PD-L1以及抑制HIF-1α可代表癌症免疫疗法的新方法。 ©2014 Noman等。

　

PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced: MDSC-mediated T cell activation

Tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumorassociated macrophages (TAMs) form an important component of the hypoxic tumor microenvironment. Here, we investigated the influence of hypoxia on immune checkpoint receptors (programmed death [PD]-1 and CTLA-4) and their respective ligands (PD-1 ligand 1 [PD-L1], PD-L2, CD80, and CD86) on MDSCs.

　

We demonstrate that MDSCs at the tumor site show a differential expression of PD-L1 as compared with MDSCs from peripheral lymphoid organ (spleen).

Hypoxia caused a rapid, dramatic, and selective up-regulation of PD-L1 on splenic MDSCs in tumor-bearing mice. This was not limited to MDSCs, as hypoxia also significantly increased the expression of PD-L1 on macrophages, dendritic cells, and tumor cells.

Furthermore, PD-L1 up-regulation under hypoxia was dependent on hypoxia-inducible factor-1α (HIF-1α) but not HIF-2α.

Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of HIF-1α to a transcriptionally active hypoxia-response element (HRE) in the PD-L1 proximal promoter. Blockade of PD-L1 under hypoxia enhanced MDSCmediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10.

Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs.

Simultaneous blockade of PD-L1 along with inhibition of HIF-1α may thus represent a novel approach for cancer immunotherapy. © 2014 Noman et al.

SOURCE:

Journal of Experimental Medicine

Volume 211, Issue 5, May 2014, Pages 781-790

　

Noman, M.Z.,  Desantis, G.,  Janji, B.,  Hasmim, M.,  Karray, S.,  Dessen, P.,  Bronte, V.,  Chouaib, S.  View Correspondence (jump link)

aUnité Institut National de la Santé et de la Recherche Médicale U753, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France

bIstituto Oncologico Veneto, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), 35128 Padua, Italy

cLaboratory of Experimental Hemato-Oncology, Department of Oncology. Public Research Center for Health (CRP-Santé), L-1526 Luxembourg City, Luxembourg

　

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473331/