Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets.
Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets.
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DOI：
10.1158/0008-5472.can-21-3840
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发表时间：
2022-11-15
期刊：
影响因子：
11.2
通讯作者：
Lathia JD
中科院分区：
文献类型：
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作者：
Bayik D;Bartels CF;Lovrenert K;Watson DC;Zhang D;Kay K;Lee J;Lauko A;Johnson S;Lo A;Silver DJ;McGraw M;Grabowski M;Mohammadi AM;Veglia F;Fan Y;Vogelbaum MA;Scacheri P;Lathia JD
表观遗传学分析揭示了细胞粘附编程作为胶质母细胞瘤中单核髓源性抑制细胞促肿瘤功能的调节因子，确定了调节免疫反应和抑制肿瘤生长的治疗靶点。在多种类型的癌症中，髓源性抑制细胞（MDSC）频率的增加与较差的结果和较差的治疗反应相关。在胶质母细胞瘤（GBM）微环境中，单核细胞(m) MDSCs是主要的亚群。然而，与粒细胞(g) MDSCs相比，肿瘤微环境中mMDSC富集的分子基础尚未确定。在这里，我们对MDSC亚群进行了首次广泛的表观遗传学分析，以定义潜在的细胞内在行为差异，并发现mmdsc中细胞粘附程序的基因可及性增强与它们在GBM模型中过继转移后的肿瘤加速能力有关。与gmdsc相比，小鼠和人mmdsc表达更高水平的整合素β1和二肽基肽酶-4 (DPP-4)，作为增强细胞粘附特征的一部分。整合素β1阻断可消除mmdsc的促肿瘤表型，并改变肿瘤微环境中的免疫谱，而DPP-4抑制剂治疗可延长临床前GBM模型的生存期。在mmdsc中靶向DPP-4可减少pERK信号及其向肿瘤细胞的迁移。这些发现揭示了MDSC亚群分子基础的根本差异，并提示整合素β1和DPP-4可能是减轻GBM中髓细胞驱动的免疫抑制的免疫治疗靶点。表观遗传学分析揭示了细胞粘附编程作为胶质母细胞瘤中单核髓源性抑制细胞促肿瘤功能的调节因子，确定了调节免疫反应和抑制肿瘤生长的治疗靶点。
Epigenetic profiling uncovers cell adhesion programming as a regulator of the tumor-promoting functions of monocytic myeloid-derived suppressor cells in glioblastoma, identifying therapeutic targets that modulate the immune response and suppress tumor growth. In multiple types of cancer, an increased frequency in myeloid-derived suppressor cells (MDSC) is associated with worse outcomes and poor therapeutic response. In the glioblastoma (GBM) microenvironment, monocytic (m) MDSCs represent the predominant subset. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared with granulocytic (g) MDSCs has yet to be determined. Here we performed the first broad epigenetic profiling of MDSC subsets to define underlying cell-intrinsic differences in behavior and found that enhanced gene accessibility of cell adhesion programs in mMDSCs is linked to their tumor-accelerating ability in GBM models upon adoptive transfer. Mouse and human mMDSCs expressed higher levels of integrin β1 and dipeptidyl peptidase-4 (DPP-4) compared with gMDSCs as part of an enhanced cell adhesion signature. Integrin β1 blockade abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment, whereas treatment with a DPP-4 inhibitor extended survival in preclinical GBM models. Targeting DPP-4 in mMDSCs reduced pERK signaling and their migration towards tumor cells. These findings uncover a fundamental difference in the molecular basis of MDSC subsets and suggest that integrin β1 and DPP-4 represent putative immunotherapy targets to attenuate myeloid cell-driven immune suppression in GBM. Epigenetic profiling uncovers cell adhesion programming as a regulator of the tumor-promoting functions of monocytic myeloid-derived suppressor cells in glioblastoma, identifying therapeutic targets that modulate the immune response and suppress tumor growth.