Abstract

The co-evolution between cancer and the immune system during metastasis is dynamic and versatile. In syngeneic mammary tumor models, we discovered unexpected functions of type I T helper cells and NK cells in shaping the metastasis process. The former prevents metastasis by promoting vessel normalization, a process involving improved pericyte attachment to endothelium, increased blood perfusion, decreased vessel permeability, and consequently mitigated hypoxia. The latter exerts selective pressures for CTC -clustering and polyclonal metastasis seeding, by eliminating single cell CTCs that have presumably lost epithelial traits. Therapies augmenting T cell and NK cell functions efficiently restrict metastases, although resistance often develops through multiple mechanisms including accumulation of myeloid-derived suppressor cells. Our research uncovered spatiotemporally specific interactions between cancer cells and various immune cells, and cries for in-depth investigations on collective activities of multiple cell types beyond cytotoxic T cells.