BCL9 regulates CD226 and CD96 checkpoints in CD8(+) T cells to improve PD-1 response in cancer.
BCL9 regulates CD226 and CD96 checkpoints in CD8(+) T cells to improve PD-1 response in cancer.
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BCL9 调节 CD8~ T 细胞中的 CD226 和 CD96 检查点以改善癌症中的 PD-1 反应
DOI：
10.1038/s41392-021-00730-0
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发表时间：
2021-08-20
影响因子：
39.3
通讯作者：
Zhu D
中科院分区：
文献类型：
--
作者：
Feng M;Wu Z;Zhou Y;Wei Z;Tian E;Mei S;Zhu Y;Liu C;He F;Li H;Xie C;Jin J;Dong J;Yang D;Yu K;Qian J;Lambrechts D;Wang MW;Zhu D
迄今为止，PD-1阻断的总体缓解率仍然不令人满意，部分原因是对肿瘤免疫微环境（TIME）的理解有限。B细胞淋巴瘤9（BCL 9）是Wnt通路的关键转录共激活因子，在癌症中高度表达。通过肿瘤中BCL 9的遗传耗竭和药理学抑制，我们发现BCL 9抑制降低了肿瘤生长，促进了CD 8 + T细胞肿瘤浸润，并增强了小鼠结肠癌模型对抗PD-1治疗的反应。为了确定BCL 9在TIME调节中的作用的潜在机制，应用单细胞RNA-seq来揭示BCL 9抑制后肿瘤免疫微环境中的细胞景观和转录差异。CD 155-CD 226和CD 155-CD 96检查点在癌细胞/CD 8 + T细胞相互作用中起关键作用。BCL 9抑制诱导CD 8 + T细胞中VAV 1的磷酸化，并增加GLI 1和PATCH表达，以促进癌细胞中CD 155的表达。在癌症基因组图谱数据库分析中，我们发现BCL 9表达与CD 155正相关，与CD 226表达负相关。BCL 9还与涉及抗PD-1治疗后患者存活的腺瘤性结肠息肉病（APC）突变有关。这项研究指出了受BCL 9抑制影响的肿瘤免疫微环境中的细胞多样性，并为BCL 9在调节CD 226和CD 96检查点中的作用提供了新的见解。
To date, the overall response rate of PD-1 blockade remains unsatisfactory, partially due to limited understanding of tumor immune microenvironment (TIME). B-cell lymphoma 9 (BCL9), a key transcription co-activator of the Wnt pathway, is highly expressed in cancers. By genetic depletion and pharmacological inhibition of BCL9 in tumors, we found that BCL9 suppression reduced tumor growth, promoted CD8+ T cell tumor infiltration, and enhanced response to anti-PD-1 treatment in mouse colon cancer models. To determine the underlying mechanism of BCL9’s role in TIME regulation, single-cell RNA-seq was applied to reveal cellular landscape and transcription differences in the tumor immune microenvironment upon BCL9 inhibition. CD155-CD226 and CD155-CD96 checkpoints play key roles in cancer cell/CD8+ T cell interaction. BCL9 suppression induces phosphorylation of VAV1 in CD8+ T cells and increases GLI1 and PATCH expression to promote CD155 expression in cancer cells. In The Cancer Genome Atlas database analysis, we found that BCL9 expression is positively associated with CD155 and negatively associated with CD226 expression. BCL9 is also linked to adenomatous polyposis coli (APC) mutation involved in patient survival following anti-PD-1 treatment. This study points to cellular diversity within the tumor immune microenvironment affected by BCL9 inhibition and provides new insights into the role of BCL9 in regulating CD226 and CD96 checkpoints
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DOI：
10.1084/jem.194.6.847
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iellem A;Mariani M;Lang R;Recalde H;Panina-Bordignon P;Sinigaglia F;D'Ambrosio D
通讯作者：
D'Ambrosio D
影响因子：
8.8
作者：
Brenner H;Chen C
通讯作者：
Chen C
影响因子：
5.5
作者：
Liang, Xinjun;Fu, Chunmei;Jiang, Aimin
通讯作者：
Jiang, Aimin
影响因子：
7.3
作者：
Gaud, Guillaume;Roncagalli, Romain;Saoudi, Abdelhadi
通讯作者：
Saoudi, Abdelhadi
影响因子：
50.3
作者：
Johnston, Robert J.;Comps-Agrar, Laetitia;Grogan, Jane L.
通讯作者：
Grogan, Jane L.