IFNβ-pSTAT1-IRF1 axis controls colorectal tumor development through induction of immunogenic Ly6C(+)myeloid cells.

It has been extensively studied that IFN-I inhibits tumor progression through their intrinsic functions in tumor cells, of which, regulating tumor cell immunogenicity is a critical way. Besides to tumor cells, myeloid cells also comprise a major component of tumor microenvironment. Nevertheless, whether IFN-I modulates the immunogenicity and function of myeloid cells in tumor microenvironment is less explored. In this research, we report that IFNβ effectively induces Ly6C(+) myeloid cell differentiation in vitro in mouse. In human PBMCs, CD14(+)CD33(+) monocytic population was consistently accumulated in the presence of IFNβ. In agreement, overexpression of IFNβ in tumor microenvironment by IFNBCOL01 treatment resulted in dramatic increase of tumor-infiltrating Ly6C(+) myeloid cells and obvious tumor growth control in vivo. Of note, overexpression of IFNβ promotes the immunogenic Ly6C(+)CD103(+)CD11c(+) subset accumulation in tumor-infiltrating myeloid cells. At the molecular level, we illustrated that the pSTAT1 directly binds to the irf1 promoter and that IRF1 directly binds to the Ly6C promoter in myeloid cells both in vitro and in vivo. Furthermore, anti-Ly6C blockade therapy significantly reversed the anti-tumor effect of IFNBCOL01 by restoring NOS2 expression and consequently suppressing T cell functions in tumor-bearing mice. Overall, our findings determine that IFNβ drives myeloid cells to differentiate into Ly6C(+) subset via the stimulation of pSTAT1-IRF1 axis in myeloid cells. In addition, IFNβ inhibits the immunosuppressive enzyme NOS2 expression in Ly6C(+) myeloid cells, which may decrease the potential immunosuppressive function of NOS2 to boost the T cell function to repress tumor, thus proposing a new perspective for the anti-tumor mechanism of IFN-I.