Department of Pathology, Soochow University Medical School, Suzhou, China.
Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Signal Transduct Target Ther. 2021 Mar 12;6(1):115. doi: 10.1038/s41392-021-00501-x.
The mechanisms and key factors involved in tumor environments for lung metastasis of CRC are still unclear. Here, using clinical samples from lung metastases of CRC patients, we found that intestinal immune network for IgA production was significantly dysregulated in lung metastases of CRC. Single-cell RNA sequencing discovered a subtype of B cells positive for Erbin, one member of the leucine-rich repeat and PDZ domain (LAP) family, was involved in the lung metastases. Erbin deletion in B cells suppressed lung metastasis of CRC in vivo. And, deletion of Erbin in B cells enhanced the killing effects of CD8 T cells on tumor cells. Mechanistically, Erbin knockout attenuated TGFβ-mediated suppression of migration of CXCR5 IgA cells and STAT6-mediated PD1 expression. Our study uncovered a key role of Erbin in regulating PD1 IgA B cells in lung metastasis of CRC. Targeting Erbin as well as combined use of neutralizing B cells and antibodies neutralizing PD1 suppresses lung metastasis of CRC in mice, suggesting the potential option for treatment of lung metastasis of CRC.
CRC 肺转移肿瘤微环境中的机制和关键因素仍不清楚。在这里，我们使用来自 CRC 肺转移患者的临床样本，发现 CRC 肺转移中肠道 IgA 产生免疫网络显著失调。单细胞 RNA 测序发现，富含亮氨酸重复和 PDZ 结构域（LAP）家族成员之一的 Erbin 阳性 B 细胞亚群参与了肺转移。B 细胞中 Erbin 的缺失抑制了 CRC 的肺转移。而且，B 细胞中 Erbin 的缺失增强了 CD8 T 细胞对肿瘤细胞的杀伤作用。在机制上，Erbin 缺失减弱了 TGFβ介导的 CXCR5 IgA 细胞迁移抑制和 STAT6 介导的 PD1 表达。我们的研究揭示了 Erbin 在调节 CRC 肺转移中 PD1 IgA B 细胞中的关键作用。靶向 Erbin 以及中和 B 细胞和中和 PD1 的抗体联合使用可抑制小鼠 CRC 的肺转移，提示这为 CRC 肺转移的治疗提供了潜在选择。
