T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy

Metastasis is the main cause of cancer-related mortality. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Here we describe a chemotherapy-induced, hostmediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and remodeling and mechanostructural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse model harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8 thorn T cells expressing LOX. Consistently, adoptive transfer of CD8 thorn T cells, but not CD4 thorn T cells or B cells, from PTX-treated mice to naxe002;eurove immunodeprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer.

Automated summary

Metastasis is a major cause of cancer-related deaths. This study found that chemotherapy can induce a host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), which facilitates cancer cell seeding and structural changes in the lungs. The research also revealed that the ECM remodeling is mediated by CD8 T cells expressing the enzyme lysyl oxidase (LOX). This study highlights the role of immune cells in regulating the ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling may be a potential therapeutic strategy for metastatic cancer.