IDO1 Signaling through GCN2 in a Subpopulation of Gr-1+ Cells Shifts the IFNγ/IL6 Balance to Promote Neovascularization
- 23 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 9 (5), 514-528
- https://doi.org/10.1158/2326-6066.cir-20-0226
Abstract
In addition to immunosuppression, it is generally accepted that MDSCs (myeloid-derived suppressor cells) also support tumor angiogenesis. The tryptophan catabolizing enzyme IDO1 (indoleamine 2,3-dioxygenase) has been implicated in promoting neovascularization through its positioning as a key regulatory node between the inflammatory cytokines IFNγ 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 was 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 the 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 anti-angiogenic effect of host IFNγ by intrinsically signaling for the production of IL6 through GCN2 (general control nonderepressible 2)-mediated activation of the ISR (integrated stress response). These findings reveal fundamental molecular and cellular insights into how IDO1 interfaces with the inflammatory milieu to promote neovascularization.Other Versions
Funding Information
- Department of Health (SAP #4100072554)
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