Single-cell transcriptome analysis reveals T-cell exhaustion in denosumab-treated giant cell tumor of bone.
Single-cell transcriptome analysis reveals T-cell exhaustion in denosumab-treated giant cell tumor of bone.
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DOI：
10.3389/fimmu.2022.934078
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
Denosumab （DMAB）是一种针对核因子κ B配体受体激活剂的人单克隆抗体，用于治疗不可切除的骨巨细胞瘤（GCTB）。然而，对DMAB治疗后gctb浸润淋巴细胞的分子和功能特征知之甚少。在这里，我们进行了单细胞RNA测序和免疫染色测定，以描绘存在和不存在DMAB的GCTB的免疫景观。我们发现枯竭的CD8+ T细胞在dmab处理的GCTB中优先富集。一种独特的m2偏斜型肿瘤相关巨噬细胞（tam）包括大多数GCTB tam。我们发现细胞因子，包括白细胞介素-10和M2 tam的抑制性受体是CD8+ T细胞衰竭的重要介质。我们进一步发现，DMAB处理显著增加GCTB细胞中骨膜蛋白（POSTN）的表达水平。此外，POSTN的表达受c-FOS信号的转录调控，并与DMAB治疗后患者的GCTB复发相关。总的来说，我们的研究结果表明，CD8+ t细胞在DMAB治疗期间经历了不被重视的衰竭，GCTB细胞来源的POSTN教育tam并建立了促进GCTB复发的微环境生态位。
Denosumab (DMAB), a human monoclonal antibody against the receptor activator of the nuclear factor-kappa B ligand, is used for the treatment for unresectable giant cell tumor of bone (GCTB). However, little is known about the molecular and functional characteristics of GCTB-infiltrating lymphocytes after DMAB treatment. Here, we performed single-cell RNA sequencing and immunostaining assays to delineate the immune landscape of GCTB in the presence and absence of DMAB. We found that exhausted CD8+ T cells were preferentially enriched in DMAB-treated GCTB. A distinct M2-skewed type of tumor-associated macrophages (TAMs) comprises the majority of GCTB TAMs. We identified cytokines, including interleukin-10, and inhibitory receptors of M2 TAMs as important mediators of CD8+ T cell exhaustion. We further revealed that DMAB treatment notably increased the expression levels of periostin (POSTN) in GCTB cells. Furthermore, POSTN expression was transcriptionally regulated by c-FOS signaling and correlated with GCTB recurrence in patients after DMAB treatment. Collectively, our findings reveal that CD8+ T-cells undergo unappreciated exhaustion during DMAB therapy and that GCTB cell-derived POSTN educates TAMs and establishes a microenvironmental niche that facilitates GCTB recurrence.
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DOI：
10.1002/advs.202101895
发表时间：
2021-10
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
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作者：
Lu B;Zou C;Yang M;He Y;He J;Zhang C;Chen S;Yu J;Liu KY;Cao Q;Zhao W
通讯作者：
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影响因子：
12.7
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Xiao Y
DOI：
10.1084/jem.189.7.1025
发表时间：
1999-04-05
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
Choi Y
影响因子：
16.6
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Gómez-Aleza C;Nguyen B;Yoldi G;Ciscar M;Barranco A;Hernández-Jiménez E;Maetens M;Salgado R;Zafeiroglou M;Pellegrini P;Venet D;Garaud S;Trinidad EM;Benítez S;Vuylsteke P;Polastro L;Wildiers H;Simon P;Lindeman G;Larsimont D;Van den Eynden G;Velghe C;Rothé F;Willard-Gallo K;Michiels S;Muñoz P;Walzer T;Planelles L;Penninger J;Azim HA Jr;Loi S;Piccart M;Sotiriou C;González-Suárez E
通讯作者：
González-Suárez E
影响因子：
4.2
作者：
Aponte-Tinao, Luis A.;Piuzzi, Nicolas S.;Farfalli, German L.
通讯作者：
Farfalli, German L.