Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses DOI
Kunle Odunsi, Feng Qian,

Amit A. Lugade

et al.

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(636)

Published: March 16, 2022

To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot, window-of-opportunity study 17 patients newly diagnosed advanced high-grade serous ovarian cancer before their standard tumor debulking surgery. Patients were treated the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, metabolomic characterization microenvironment was undertaken baseline posttreatment biopsies. inhibition resulted efficient kynurenine pathway tryptophan degradation accompanied by metabolic adaptation that shunted catabolism toward serotonin pathway. This elevated nicotinamide adenine dinucleotide (NAD + ), which reduced T cell proliferation function. Because NAD metabolites could be ligands for purinergic receptors, investigated impact blocking receptors presence or absence on function our mouse model. We demonstrated A2a A2b receptor antagonists, SCH58261 PSB1115, respectively, rescued -mediated suppression Combining A2a/A2b improved survival boosted antitumor immune signature mice overexpressing cancer. These findings elucidate downstream adaptive consequences cancers may undermine responses microenvironment.

Language: Английский

IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression DOI Creative Commons
Ahmed Sadik, Luis F. Somarribas Patterson, Selcen Öztürk

et al.

Cell, Journal Year: 2020, Volume and Issue: 182(5), P. 1252 - 1270.e34

Published: Aug. 19, 2020

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation activity its upstream enzymes across human cancers. A pan-tissue signature, derived natural language processing, revealed that 32 entities, interleukin-4-induced-1 (IL4I1) associates more frequently with than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates through generation indole metabolites kynurenic acid. It reduced survival in glioma patients, promotes cancer cell motility, adaptive immunity, thereby enhancing progression chronic lymphocytic leukemia (CLL) mice. Immune checkpoint blockade (ICB) induces IL4I1. As inhibitors do not block IL4I1, may explain failure clinical studies combining ICB inhibition. Taken together, opens new avenues for therapy.

Language: Английский

Citations

382
Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer DOI Creative Commons
Joseph Tintelnot, Yang Xu, Till Robin Lesker

et al.

Nature, Journal Year: 2023, Volume and Issue: 615(7950), P. 168 - 174

Published: Feb. 22, 2023

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing high incidence of metastatic disease and limited responses treatment1,2. Less than half all patients respond primary treatment for PDAC, chemotherapy3,4, genetic alterations alone cannot explain this5. Diet an environmental factor that can influence response therapies, but its role in PDAC unclear. Here, using shotgun metagenomic sequencing metabolomic screening, we show microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) enriched who treatment. Faecal microbiota transplantation, short-term dietary manipulation oral 3-IAA administration increase efficacy chemotherapy humanized gnotobiotic mouse models PDAC. Using a combination loss- gain-of-function experiments, licensed neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which with induces downregulation reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 7. All this results accumulation ROS autophagy cells, compromises their metabolic fitness and, ultimately, proliferation. In humans, observed significant correlation between levels therapy two independent cohorts. summary, identify has clinical implications provide motivation considering nutritional interventions during cancer.

Language: Английский

Citations

251
Activatable Polymer Nanoenzymes for Photodynamic Immunometabolic Cancer Therapy DOI

Ziling Zeng,

Chi Zhang, Jing Li

et al.

Advanced Materials, Journal Year: 2020, Volume and Issue: 33(4)

Published: Dec. 11, 2020

Abstract Tumor immunometabolism contributes substantially to tumor proliferation and immune cell activity, thus plays a crucial role in the efficacy of cancer immunotherapy. Modulation boost immunotherapy is mostly based on small‐molecule inhibitors, which often encounter issues off‐target adverse effects, drug resistance, unsustainable response. In contrast, enzymatic therapeutics can potentially bypass these limitations but has been less exploited. Herein, an organic polymer nanoenzyme (SPNK) with near‐infrared (NIR) photoactivatable immunotherapeutic effects reported for photodynamic immunometabolic therapy. SPNK composed semiconducting core conjugated kynureninase (KYNase) via PEGylated singlet oxygen ( 1 O 2 ) cleavable linker. Upon NIR photoirradiation, generates not only exert effect induce immunogenic death cancer, also unleash KYNase trigger its activity degrade immunosuppressive kynurenine (Kyn). Such combinational mediated by promotes infiltration effector T cells, enhances systemic antitumor immunity, ultimately permits inhibition both primary distant tumors living mice. Therefore, this study provides promising approach toward remotely controlled immunomodulation improved anticancer

Language: Английский

Citations

244
Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook DOI Creative Commons
Lena Horvath, Bernard Thienpont, Liyun Zhao

et al.

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Sept. 11, 2020

Abstract Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging overall survival (OS) advanced stage patients. Over recent years IO been broadly integrated into first-line setting non-oncogene driven NSCLC, either in combination with chemotherapy, or selected patients PD-L1 high expression as monotherapy. Still, a significant proportion suffer from disease progression. A better understanding resistance mechanisms depicts central goal to avoid overcome and improve patient outcome. We here review major cellular molecular pathways within tumor microenvironment (TME) that may impact evolution resistance. summarize upcoming treatment options after including novel targets (e.g. RIG-I, STING) well interesting combinational approaches such combined anti-angiogenic agents metabolic IDO-1, adenosine signaling, arginase). By discussing fundamental mode action TME, we aim understand manage seed new ideas for effective therapeutic concepts.

Language: Английский

Citations

199
Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy DOI Creative Commons
Yu Fujiwara, Shumei Kato, Mary Nesline

et al.

Cancer Treatment Reviews, Journal Year: 2022, Volume and Issue: 110, P. 102461 - 102461

Published: Aug. 30, 2022

Strategies for unlocking immunosuppression in the tumor microenvironment have been investigated to overcome resistance first-generation immune checkpoint blockade with anti- programmed cell death protein 1 (PD-1)/ death-ligand (PD-L1) and anti-cytotoxic T-lymphocyte associated 4 (CTLA-4) agents. Indoleamine 2,3-dioxygenase (IDO) 1, an enzyme catabolizing tryptophan kynurenine, creates immunosuppressive environment preclinical studies. Early phase clinical trials investigating inhibition of IDO1, especially together blockade, provided promising results. Unfortunately, 3 trial IDO1 inhibitor epacadostat combined PD-1 pembrolizumab did not show benefit when compared monotherapy patients advanced malignant melanoma, which dampened enthusiasm IDO inhibitors. Even so, several molecules, such as aryl hydrocarbon receptor 2,3-dioxygenase, were reported additional potential targets modulation pathway, might enhance effectiveness. Furthermore, combination pathway agents inhibiting other signals, those generated by PIK3CA mutations that may accompany upregulation, be a novel way activity. Importantly, expression level varies type among same type, suggesting patient selection based on levels warranted trials.

Language: Английский

Citations

173
Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer DOI Creative Commons
Lukas Lanser,

Patricia Kink,

Eva Maria Egger

et al.

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Feb. 21, 2020

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

Language: Английский

Citations

140
Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications DOI Creative Commons
Mustafa N. Mithaiwala, Danielle Santana‐Coelho, Grace A. Porter

et al.

Cells, Journal Year: 2021, Volume and Issue: 10(6), P. 1548 - 1548

Published: June 19, 2021

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around globe. The development therapeutic strategies for CNS conditions has suffered due to poor understanding underlying pathologies that manifest them. Understanding common etiological origins at cellular molecular level is essential enhance efficacious targeted treatment options. Over years, neuroinflammation been posited as link between multiple neurological, neurodegenerative neuropsychiatric disorders. Processes precipitate neuroinflammatory including genetics, infections, physical injury psychosocial factors, like stress trauma, closely dysregulation in kynurenine pathway (KP) tryptophan metabolism possible pathophysiological factor 'fuel fire' diseases. In this study, we aim review emerging evidence provide mechanistic insights different disorders, KP. We thorough overview branches KP pertinent disease pathology have implications selected strategies.

Language: Английский

Citations

119
Immune regulation through tryptophan metabolism DOI Creative Commons
Su‐Kil Seo, Byungsuk Kwon

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(7), P. 1371 - 1379

Published: July 3, 2023

Amino acids are fundamental units of molecular components that essential for sustaining life; however, their metabolism is closely interconnected to the control systems cell function. Tryptophan (Trp) an amino acid catabolized by complex metabolic pathways. Several resulting Trp metabolites bioactive and play central roles in physiology pathophysiology. Additionally, various physiological functions mutually regulated gut microbiota intestine coordinately maintain intestinal homeostasis symbiosis under steady state conditions during immune response pathogens xenotoxins. Cancer inflammatory diseases associated with dysbiosis- host-related aberrant inactivation aryl hydrocarbon receptor (AHR), which a several metabolites. In this review, we focus on mechanisms through converges AHR activation modulation function restoration tissue how these processes can be targeted using therapeutic approaches cancer autoimmune diseases.

Language: Английский

Citations

103
Emerging therapies in cancer metabolism DOI Creative Commons
Yi Xiao, Tian‐Jian Yu, Ying Xu

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(8), P. 1283 - 1303

Published: Aug. 1, 2023

Language: Английский

Citations

96
The expanding role for small molecules in immuno-oncology DOI
Rienk Offringa,

Lisa Kötzner,

Bayard R. Huck

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(11), P. 821 - 840

Published: Aug. 18, 2022

Language: Английский

Citations

86