Tumor-derived miR-126 promotes tumor progression through immune modulation beyond the local tumor environment.

Epidermal growth factor-like domain 7 (EGFL7) was discovered as an extracellular matrix protein with an EGF-like domain and angiogenic and vasculogenic functions. It has also been shown to play a role in immunological evasion of tumor cells through attenuation of extravasation of immune cells by reducing the expression of cell adhesion molecules on vascular endothelial cells. Furthermore, microRNA-126 (miR-126), which is encoded within the intron of Egfl7, has been reported to be a vasculogenic factor. However, its immune-related functions in tumors remain unclear. Here, we examined the roles of tumor-derived EGFL7 and miR-126 in in vivo tumor progression using Egfl7/Mir-126 knockout and rescue tumor cell lines. Tumor growth was significantly suppressed in Egfl7/Mir-126-deficient cells and was restored by re-expression of miR-126, but not EGFL7. These differences in in vivo tumor growth were not observed in immunodeficient mice, suggesting the involvement of the adaptive immune system. CD4+ or CD25+ cell depletion suppressed the growth of miR-126-expressing tumors, whereas CD8+ cell depletion enhanced the growth of miR-126-deficient tumors. Histological analysis revealed an increased Foxp3+/CD8+ cell ratio in miR-126-expressing tumors during the early phase of tumor establishment. Bilateral tumor models further demonstrated that miR-126-expressing tumors promoted the growth of contralateral miR-126-deficient tumors, and a similar effect was observed using apoptotic miR-126-expressing tumor cells In vitro analyses using extracellular vesicles derived from dying tumor cells showed the transfer of miR-126 to CD4+ T cells and a higher proportion of Foxp3+ cells. Together, these findings suggest that tumor-derived miR-126 promotes tumor progression through non-local immune modulation, potentially involving maintenance of Treg-associated populations.