Deciphering the pathways that lead to IDO1 constitutive expression in human cancer cells
(2017)
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- Tumours use various mechanisms to avoid immune destruction. One of these is the degradation of the essential amino acid, tryptophan. This reaction is mediated by indoleamine 2,3-dioxygenase (IDO1) and leads to proliferation arrest of anti-tumour T cells. In cancer cells, the induction of IDO1 expression by IFNγ is considered as an adaptive resistance mechanism. However, cancer cells also express IDO1 constitutively, but the signalling pathways leading to such expression and its contribution to an immunosuppressive environment were not known. Here, we show that Cyclooxygenase-2 (COX-2) expression drives constitutive expression of IDO1 in human tumour cells through production of prostaglandin E2, which activates the PKC and PI3K pathways. Treatment of mice with a COX-2 inhibitor promoted immune rejection of IDO1+ human tumour xenografts in immunodeficient mice reconstituted with human allogeneic lymphocytes, and was associated with an infiltration of CD3+ and CD8+ cells. Our results highlight the contribution of constitutive IDO1 expression in the lack of T-cell infiltration in “cold” tumours, which fail to respond to immunotherapy.
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Hennequart, M. (2017). Deciphering the pathways that lead to IDO1 constitutive expression in human cancer cells. https://hdl.handle.net/2078.5/177541