IDO1 signaling through GCN2 in a subpopulation of Gr-1þ cells shifts the IFNg/IL6 balance to promote neovascularization

Abstract

In addition to immunosuppression, it is generally accepted that myeloid-derived suppressor cells (MDSC) also support tumor angiogenesis. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1) has been implicated in promoting neovascularization through its positioning as a key regulatory node between the inflammatory cytokines IFNg and IL6. Here, we report that within the heterogeneous expanse of Gr-1þ MDSCs, both IDO1 expression and the ability to elicit neovascularization in vivo were associated with a minor subset of autofluorescent, CD11blo cells. IDO1 expression was further restricted to a discrete, CD11c and asialo-GM1 double-positive subpopulation of these cells, designated here as IDVCs (IDO1-dependent vascularizing cells), due to the dominant role that IDO1 activity in these cells was found to play in promoting neovascularization. Mechanistically, the induction of IDO1 in IDVCs provided a negative-feedback constraint on the antiangiogenic effect of host IFNg by intrinsically signaling for the production of IL6 through general control nonderepressible 2 (GCN2)–mediated activation of the integrated stress response. These findings reveal fundamental molecular and cellular insights into how IDO1 interfaces with the inflammatory milieu to promote neovascularization.