Host <i>IDO2</i> Gene Status Influences Tumor Progression and Radiotherapy Response in <i>KRAS</i>-Driven Sporadic Pancreatic Cancers

Muller, Alexander J.; Sutanto‐Ward, Erika; DuHadaway, James B.; Nagatomo, Kei; Londin, Eric; O’Hayer, Kevin; Cozzitorto, Joseph A.; Lavu, Harish; Yeo, Theresa P.; Curtis, Mark; Villatoro, Tatiana; Leiby, Benjamin E.; Mandik-Nayak, Laura; Winter, Jordan M.; Yeo, Charles J.; Prendergast, George C.; Brody, Jonathan R.

doi:10.1158/1078-0432.ccr-18-0814

Cited by 45 publications

(52 citation statements)

References 47 publications

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“…The precise effect of rs16888361 on IDO2 expression is currently under investigation. Interestingly, a pro-inflammatory role of IDO2 has been recently suggested in a study evaluating the influence of IDO2 gene status in tumor progression and radiotherapy response in pancreatic ductal adenocarcinoma (PDAC) (35). In particular, an IDO2 deficient status, while being significantly absent in females with PDAC, was associated with an improved immune signature, further supporting the hypothesis that IDO2 may promote inflammatory responses, and this was associated with an improved survival in response to adjuvant radiotherapy (35).…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans

et al. 2019

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Aspergillus is the causative agent of human diseases ranging from asthma to invasive infection. Genetic and environmental factors are crucial in regulating the interaction between the host and Aspergillus . The role played by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the first and rate-limiting step of tryptophan catabolism along the kynurenine pathway, is increasingly being recognized, but whether and how genetic variation of IDO1 influences the risk of aspergillosis in susceptible patients is incompletely understood. In addition, whether the closely related protein IDO2 plays a similar role remains unexplored. In the present study, we performed genetic association studies in two different cohorts of susceptible patients [cystic fibrosis (CF) patients and recipients of hematopoietic stem cell transplantation (HSCT)], and identified IDO1 polymorphisms that associate with the risk of infection in both cohorts. By using human bronchial epithelial cells and PBMC from CF and HSCT patients, respectively, we could show that the IDO1 polymorphisms appeared to down-modulate IDO1 expression and function in response to IFNγ or Aspergillus conidia, and to associate with an increased inflammatory response. In contrast, IDO2 polymorphisms, including variants known to profoundly affect protein expression and function, were differently associated with the risk of aspergillosis in the two cohorts of patients as no association was found in CF patients as opposed to recipients of HSCT. By resorting to a murine model of bone marrow transplantation, we could show that the absence of IDO2 more severely affected fungal burden and lung pathology upon infection with Aspergillus as compared to IDO1, and this effect appeared to be linked to a deficit in the antifungal effector phagocytic activity. Thus, our study confirms and extends the role of IDO1 in the response to Aspergillus , and shed light on the possible involvement of IDO2 in specific clinical settings.

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Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans

et al. 2019

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“…Although IDO2 is expressed by cancer cells, it does not contribute to the accumulation of Trp metabolites to the same extent as IDO1 (170,171). However, it was recently implicated that IDO2 affects B cell-mediated autoimmunity (172), and also contributes to carcinogenesis in models of pancreatic cancers (173). Interestingly, IDO2-deficiency was predictive for diseasefree survival in patients receiving adjuvant radiotherapy (173).…”

Section: Indoleamine 23-dioxygenase 2 Tryptophan 23-dioxygenase Amentioning

confidence: 99%

“…However, it was recently implicated that IDO2 affects B cell-mediated autoimmunity (172), and also contributes to carcinogenesis in models of pancreatic cancers (173). Interestingly, IDO2-deficiency was predictive for diseasefree survival in patients receiving adjuvant radiotherapy (173).…”

Section: Indoleamine 23-dioxygenase 2 Tryptophan 23-dioxygenase Amentioning

confidence: 99%

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

et al. 2020

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Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-γ) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohydrolase I to form neopterin. High neopterin concentrations as well as an increased kynurenine to tryptophan ratio (Kyn/Trp) in the blood of cancer patients are predictive for a worse outcome. Inflammation-mediated tryptophan catabolism along the kynurenine pathway is related to fatigue and anemia as well as to depression and a decreased QoL in patients with solid tumors. In fact, enhanced tryptophan breakdown might greatly contribute to the development of anemia, fatigue, and depression in cancer patients. IDO activation and stimulation of the kynurenine pathway exert immune regulatory mechanisms, which may impair anti-tumor immune responses. In addition, tumor cells can degrade tryptophan to weaken immune responses directed against them. High IDO expression in the tumor tissue is associated with a poor prognosis of patients. The efficiency of IDO-inhibitors to inhibit cancer progression is currently tested in combination with established chemotherapies and with immune checkpoint inhibitors. Inflammation-mediated tryptophan catabolism and its possible influence on the development and persistence of anemia, fatigue, and depression in cancer patients are discussed.

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“…Interestingly, recently Nevler et al have shown that Ido2‐knockout mice are less likely to have pancreatic ductal adenocarcinoma. Furthermore, in patients, the biallelic occurrence of either of the 2 IDO2‐inactivating SNPs is also significantly associated with markedly improved disease‐free survival in response to adjuvant radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3‐dioxygenase 2 depletion suppresses tumor growth in a mouse model of Lewis lung carcinoma

et al. 2019

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Tryptophan metabolism is important to induce immune tolerance in tumors. To date, 3 types of tryptophan‐metabolizing enzymes have been identified: indoleamine 2,3‐dioxygenase 1 and 2 (IDO1 and IDO2) and tryptophan 2,3‐dioxygenase 2. Numerous studies have focused on IDO1 as its expression is enhanced in various cancers. Recently, IDO2 has been identified as a tryptophan‐metabolizing enzyme that is involved in several immune functions and expressed in cancers such as pancreatic cancer. However, the biological role of IDO2 in the induction of immune tolerance in tumors has not yet been reported. In the present study, we examined the effects of Ido2 depletion on tumor growth in a mouse model of Lewis lung carcinoma by using Ido2‐knockout mice. Ido2‐knockout mice had reduced tumor volumes compared to WT mice. Furthermore, Ido2 depletion altered the tumor microenvironment, such as tryptophan accumulation and kynurenine reduction, leading to enhancement of immune cell invasion. Finally, enzyme‐linked immunospot assay revealed that Ido2 depletion enhanced γ‐interferon secretion in the tumor. In conclusion, Ido2 is an important immune regulator in the tumor microenvironment. Our data indicate that IDO2 is a potential target for cancer treatment and drug development.

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Host IDO2 Gene Status Influences Tumor Progression and Radiotherapy Response in KRAS-Driven Sporadic Pancreatic Cancers

Cited by 45 publications

References 47 publications

Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans

Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

Indoleamine 2,3‐dioxygenase 2 depletion suppresses tumor growth in a mouse model of Lewis lung carcinoma

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