Targeting Erbin in B cells for therapy of lung metastasis of colorectal cancer

Tong Shen,Ling-Dong Cai,Jian-Ming Li,Jian-Ming Li,Jian-Ming Li,Shi Li,Shi Li,Shi Li,Chu-Yi Wang,Youlutuziayi Rixiati,Yuan-Yuan Zhao,Jing-Lin Liu

doi:10.1038/s41392-021-00501-x

Abstract

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.

Highlights

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide.[1]
B cells related genes and pathways are significantly enriched in CRC patients with or without distant metastasis To find the key gene and pathway involved in metastasis of CRC, we performed transcriptome sequencing to detect differentially expressed genes between tumors and adjacent tissues from CRC cancer patients with or without distant metastasis (Supplementary Table S2a, b)
Received: 29 July 2020 Revised: 15 December 2020 Accepted: 13 January 2021 concentrated in the normal tissue (Norm), partly aggregated in invasion margin (IM), and rarely IMag Mouse B Lymphocyte Enrichment Kit and analyzed these appeared at CT of the tumors (Supplementary Fig. S1a, d)

Summary

Introduction

The mechanisms for lung metastasis of CRC are still not well-studied.[6] The lung has its own characteristics in tissue components including airway epithelial cells (AECs), interstitial structural cells, endothelial cells, and various inflammatory cells, such as macrophages, neutrophils, and lymphocytes. Under physiological conditions, both the innate and acquired immune system in the lung microenvironment play the key roles in maintaining tissue homeostasis. In some pathological conditions such as cancer progression, the homeostasis of lung is greatly destroyed.[7] the key factors in lung microenvironment involved in lung metastases of CRC are still uncharacterized

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Results

Conclusion