Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity

Sharma, Madhav; Pacholczyk, Rafał; Shi, Huidong; Berrong, Zuzana; Zakharia, Yousef; Greco, Austin; Chang, Chang Sheng S.; Eathiraj, Sudharshan; Kennedy, Eugene P.; Cash, Thomas F.; Bollag, Roni J.; Kolhe, Ravindra; Sadek, Ramses; McGaha, Tracy L.; Rodríguez, Paulo C.; Mandula, Jessica; Blazar, Bruce R.; Johnson, Theodore S.; Munn, David H.

doi:10.1016/j.immuni.2021.09.005

Cited by 38 publications

(17 citation statements)

References 69 publications

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“…One mechanism by which DCs regulate tolerance involves the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 is a tryptophan (Trp)-metabolizing enzyme, which exerts potent immunoregulatory effects when expressed in DCs ( Grohmann et al., 2003 ; Sharma et al., 2021 ). IDO1 is the rate-limiting enzyme in the Trp metabolic pathway, which produces a series of immunoregulatory molecules, known as kynurenines ( Mellor and Munn, 2004 ; Puccetti and Grohmann, 2007 ; Terness et al., 2002 ).…”

Section: Introductionmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

et al. 2022

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“…111 Nevertheless, many effective combination therapies related to IDO1 or TDO inhibitors have been observed in preclinical studies, including the combination therapy with DNA-damaging agents, molecular targeted drugs, radiotherapy and chemoradiotherapy, etc. [112][113][114] Evidence continues to grow to support these combinations, and some of them are undergoing clinical evaluation (Tables 1-3). Moreover, IDO1/ TDO dual-target inhibitor combined with anti-PD-1 or anti-PD-L1 antibody is also an attractive combination that is worthy to be further explored.…”

Section: Discussionmentioning

confidence: 99%

Targeting Indoleamine Dioxygenase and Tryptophan Dioxygenase in Cancer Immunotherapy: Clinical Progress and Challenges

Peng¹,

Zhao²,

Liu³

et al. 2022

DDDT

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Indoleamine 2.3-dioxygenases (IDO1/2) and tryptophan 2.3-dioxygenase (TDO) are the initial and rate-limiting enzymes in tryptophan metabolism, which play an essential role in mediating immunosuppression in tumor microenvironment. Accumulating evidence has indicated that both IDO1 and TDO are highly expressed in many malignant tumors, and their expression is generally associated with reduced tumor-infiltrating immune cells, increased regulatory T-cell infiltration, as well as cancer progression and poor prognosis for malignancies. A large number of IDO1 and TDO inhibitors have been screened or synthesized in the last two decades. Thus far, at least 12 antagonists targeting IDO1 and TDO have advanced to clinical trials. In this account, we conducted a comprehensive review of the development of IDO1 and TDO inhibitors in cancer immunotherapy, particularly their clinical research progress, and presented the current challenges and corresponding solutions.

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“…After loading the Huh7-associated antigens within 48 hours, the DCs were incubated as semimature DC (semiDC). The mDCs were harvested after 24 hours interventions by KU0063794 and/or matrine [ 5 ].…”

Section: Methodsmentioning

confidence: 99%

Matrine Combined with Mammalian Target of Rapamycin Inhibitor Enhances Anti-Tumor Efficacy of dendritic cell Vaccines in hepatocellular carcinoma

Zhou

Zhang³

et al. 2022

Bioengineered

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Dendritic cells (DCs), as the most important antigen-presenting cells, play a crucial role in T cell activation. The latest research showed that inhibition of the mammalian target of rapamycin (mTOR) could enhance DCs maturation, promoting antigen presentation. Matrine has been identified as one of the key alkaloids isolated from the roots of Sophora flavescens . In present study, we combined matrine and mTOR inhibitor KU0063794 to observe the DCs functions, especially the antigen presentation ability. DCs were activated by phosphate-buffered saline (PBS), lipopolysaccharide (LPS), LPS+KU0063794, LPS+Matrine, and LPS+KU0063794+Matrine. The surface markers in DCs, proliferation of T cells and cytokines were detected by flow cytometry, cell counting kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA), respectively. The lactate dehydrogenase (LDH) release test was used to detect the antitumor efficacy. The tumor growth curves were plotted by calculating tumor volume. The apoptosis was detected by Terminal-deoxynucleoitidyl Transferase-Mediated Nick End Labeling (TUNEL) method. Matrine combined with KU0063794 could enhance the maturity of DCs, T cells proliferation and cytokines secretion ( P < 0.05). The cytotoxic T lymphocytes (CTL) killing efficacy of LPS+KU0063794+Matrine group was higher than other groups (P < 0.05). In vivo , the tumor weights and volumes in LPS+KU0063794+Matrine group were lower than other groups. The detections of tumor apoptosis were increased in LPS+KU0063794+Matrine group ( P < 0.05). DC vaccine with mTOR inhibitor and matrine could significantly improve the efficacy of antitumor immunity in vitro and vivo. These findings illustrated that mTOR inhibitor and matrine, as two immunomodulators, could enhance DC activation and differentiation.

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Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity

Cited by 38 publications

References 69 publications

Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication

Targeting Indoleamine Dioxygenase and Tryptophan Dioxygenase in Cancer Immunotherapy: Clinical Progress and Challenges

Matrine Combined with Mammalian Target of Rapamycin Inhibitor Enhances Anti-Tumor Efficacy of dendritic cell Vaccines in hepatocellular carcinoma

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