IDO1 Signaling through GCN2 in a Subpopulation of Gr-1+ Cells Shifts the IFNγ/IL6 Balance to Promote Neovascularization

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 IFN gamma and IL6. Here, we report that within the heterogeneous expanse of Gr-1(+) MDSCs, both IDO1 expression and the ability to elicit neovascularization in vivo were associated with a minor subset of autofluorescent, CD11b(lo) 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 IFN gamma 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.

Automated summary

The study found that IDO1 expression and the ability to induce neovascularization in MDSCs were primarily associated with a specific subset of cells, designated as IDVCs. The dominant role of IDO1 activity in these cells provided a negative-feedback constraint on the antiangiogenic effect of host IFNγ.