IDO1 impairs NK cell cytotoxicity by decreasing NKG2D/NKG2DLs via promoting miR-18a.

Background: Indoleamine-2,3-dioxygenase 1 (IDO1) is an important enzyme for altering the tumour microenvironment and assisting tumour cells to escape the immune system.

Results: In this study, a significant reduction in NK cell cytotoxicity that was associated with a high expression of IDO1 in a reconstructed tumour microenvironment was observed. In a co-culture system of tumour cell culture supernatant (TSN) and murine NK cell, IDO1 was substantially increased, while NKG2D was markedly downregulated in NK cells. Based on computational predictions, miR-18a, which has two definite binding sites consisting of the 3'UTR of NKG2D and the 3'UTR of NKG2D ligand (Mult-1), was suspected to be a negative regulator of which its conjoined. As expected, the IDO1 could promote the expression of miR-18a and promote the downregulation effect of miR-18a on NKG2D and NKG2DL, and INCB024360 (INCB) could reverse the result. For digging the mechanism deeper, we authenticated IDO1 promoted the combination of miR-18a and AGO2 after argonaute 2 (AGO2) co-immunoprecipitation, which then degraded Mult-1 mRNA and inhibited the translation of it, further destructing NK cell cytotoxicity.

Conclusion: Our findings revealed a new regulatory axis, IDO1/miR-18a/NKG2D/NKG2DL, in the regulation of NK cell function. This may provide insight into the mechanism of the priming effect of IDO1 inhibitors and miR-18a interference, then elicit possible new methods of cancer treatment.