Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells

Abstract

The tryptophan-degrading enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a plastic immune checkpoint molecule that potently orchestrates immune responses within the tumor microenvironment (TME). As a heme-containing protein, IDO1 catalyzes the conversion of the essential amino acid tryptophan into immunoactive metabolites, called kynurenines. By depleting tryptophan and enriching the TME with kynurenines, IDO1 catalytic activity shapes an immunosuppressive TME. Accordingly, the inducible or constitutive IDO1 expression in cancer correlates with a negative prognosis for patients, representing one of the critical tumor-escape mechanisms. However, clinically trialed IDO1 catalytic inhibitors disappointed the expected anti-tumor efficacy. Interestingly, the non-enzymatic apo-form of IDO1 is still active as a transducing protein, capable of promoting an immunoregulatory phenotype in dendritic cells (DCs) as well as a pro-tumorigenic behavior in murine melanoma. Moreover, the IDO1 catalytic inhibitor epacadostat can induce a tolerogenic phenotype in plasmacytoid DCs, overcoming the catalytic inhibition of IDO1. Based on this recent evidence, IDO1 plasticity was investigated in the human ovarian cancer cell line, SKOV-3, that constitutively expresses IDO1 in a dynamic balance between the holo- and apo-protein, and thus potentially endowed with a dual function (i.e., enzymatic and non-enzymatic). Besides inhibiting the catalytic activity, epacadostat persistently stabilizes the apo-form of IDO1 protein, favoring its tyrosine-phosphorylation and promoting its association with the phosphatase SHP-2. In SKOV-3 cells, both these early molecular events activate a signaling pathway transduced by IDO1 apo-protein, which is independent of its catalytic activity and contributes to the tumorigenic phenotype of SKOV-3 cells. Overall, our findings unveiled a new mechanism of action of epacadostat on IDO1 target, repositioning the catalytic inhibitor as a stabilizer of the apo-form of IDO1, still capable of transducing a pro-tumorigenic pathway in SKOV-3 tumor. This mechanism could contribute to clarify the lack of effectiveness of epacadostat in clinical trials and shed light on innovative immunotherapeutic strategies to tackle IDO1 target.

Association of Indoleamine 2,3-Dioxygenase (IDO) Activity with Outcome after Cardiac Surgery in Adult Patients

“…In view of these findings, we can infer that IDO plays an important role in the complex interplay of postoperative immunomodulation after cardiac surgery. This is interesting, as IDO can be selectively targeted and inhibited [ 3 , 4 , 30 , 31 , 32 ], and therefore a therapeutic intervention might potentially mitigate postoperative complications. Nevertheless, we were not able to associate perioperative metabolite dynamics with clinical outcome measures in an exploratory analysis.…”

“…This immune response is fueled by multiple factors such as the surgical trauma itself, blood interaction with extracorporeal circuits, and reperfusion injury [ 27 ], and has repeatedly been shown to influence postoperative outcomes [ 27 , 28 , 29 ]. IDO’s involvement in inflammatory responses and in conditions associated with heightened immune activation, such as CPB surgery, might serve as an immune marker and potential therapeutic target [ 3 , 4 , 30 , 31 , 32 ].…”

Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull’s eye for targeted therapy?

“…Then taking advantage of already-elevated MAPK levels in drugresistant ovarian cancer cells, elaiophylin overcame resistance to chemotherapy in ovarian cancer. Furthermore, very recently, Rossini et al (142) demonstrated that tyrosine phosphorylation and the association of indoleamine 2,3-dioxygenase 1 (IDO1) with SHP2 were significantly increased in SKOV-3 cells in response to the IDO1-inhibitor and -stabilizer epacadostat. Meanwhile, in SKOV-3 cells treated with epacadostat the signaling triggered by the transducing molecular complex IDO1-SHP2 accelerates the migratory capacity and the colony-forming ability of SKOV-3 cells, suggesting a pro-tumorigenic phenotype.…”