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Inhibition of indoleamine 2,3-dioxygenase 1 synergizes with oxaliplatin for efficient colorectal cancer therapy.

ABSTRACT: We investigated the immunogenic cell death provoked by oxaliplatin (OXA) and the involvement of OXA-induced immunosuppression in colorectal cancer. Immune-proficient or -deficient mice were employed to evaluate the therapeutic effects of OXA. Immunogenic cell death was characterized by cell-surface calreticulin, cytosol-translocated high migration rate group protein B1 (HMGB1), and secretory ATP content. Bone marrow-derived dendritic cell (BMDC) maturation and CD8⁺ T cell expansion were measured by flow cytometry. Expression of immunosuppressive genes was quantified by both RT-PCR and western blots. The proliferative and apoptotic indexes of xenograft tumors were evaluated by immunohistochemistry and TUNEL assays, respectively. The secretory cytokines were measured with ELISA. OXA induced immunogenic cell death of murine colorectal cancer, which greatly depended on the host immune response. OXA-pretreated CT26 cells promoted BMDC maturation and CD8⁺ T cell expansion. OXA significantly upregulated indoleamine 2,3-dioxygenase 1 (IDO1) in patient-derived colorectal cancer cells and in combination with the IDO1-specific inhibitor, NLG919, suppressed tumor progression. Simultaneous administration with both OXA and NLG919 greatly promoted CD8⁺ T cell infiltration and decreased immunosuppressive cytokine transforming growth factor ? (TGF-?) production, whereas increased immunostimulatory cytokines interleukin (IL)-12p70 and interferon (IFN)-?. We demonstrated the upregulation of IDO1 by OXA, which combined with the IDO1 inhibitor, tremendously potentiated therapeutic effects of OXA against colorectal cancer.

SUBMITTER: Miao X

PROVIDER: S-EPMC7889448 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Inhibition of indoleamine 2,3-dioxygenase 1 synergizes with oxaliplatin for efficient colorectal cancer therapy.

Miao Xiaofei X Zhang Ye Y Li Zengyao Z Huang Longchang L Xin Taojian T Shen Renhui R Wang Tong T

Molecular therapy. Methods & clinical development 20210105

We investigated the immunogenic cell death provoked by oxaliplatin (OXA) and the involvement of OXA-induced immunosuppression in colorectal cancer. Immune-proficient or -deficient mice were employed to evaluate the therapeutic effects of OXA. Immunogenic cell death was characterized by cell-surface calreticulin, cytosol-translocated high migration rate group protein B1 (HMGB1), and secretory ATP content. Bone marrow-derived dendritic cell (BMDC) maturation and CD8<sup>+</sup> T cell expansion we ...[more]

PMID: 33665222

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Project description:Indoleamine 2,3-dioxygenase catalyzes the O(2)-dependent oxidation of L-tryptophan (L-Trp) to N-formylkynurenine (NFK) as part of the kynurenine pathway. Inhibition of enzyme activity at high L-Trp concentrations was first noted more than 30 years ago, but the mechanism of inhibition has not been established. Using a combination of kinetic and reduction potential measurements, we present evidence showing that inhibition of enzyme activity in human indoleamine 2,3-dioxygenase (hIDO) and a number of site-directed variants during turnover with L-tryptophan (L-Trp) can be accounted for by the sequential, ordered binding of O(2) and L-Trp. Analysis of the data shows that at low concentrations of L-Trp, O(2) binds first followed by the binding of L-Trp; at higher concentrations of L-Trp, the order of binding is reversed. In addition, we show that the heme reduction potential (E(m)(0)) has a regulatory role in controlling the overall rate of catalysis (and hence the extent of inhibition) because there is a quantifiable correlation between E(m)(0) (that increases in the presence of L-Trp) and the rate constant for O(2) binding. This means that the initial formation of ferric superoxide (Fe(3+)-O(2)(•-)) from Fe(2+)-O(2) becomes thermodynamically less favorable as substrate binds, and we propose that it is the slowing down of this oxidation step at higher concentrations of substrate that is the origin of the inhibition. In contrast, we show that regeneration of the ferrous enzyme (and formation of NFK) in the final step of the mechanism, which formally requires reduction of the heme, is facilitated by the higher reduction potential in the substrate-bound enzyme and the two constants (k(cat) and E(m)(0)) are shown also to be correlated. Thus, the overall catalytic activity is balanced between the equal and opposite dependencies of the initial and final steps of the mechanism on the heme reduction potential. This tuning of the reduction potential provides a simple mechanism for regulation of the reactivity, which may be used more widely across this family of enzymes.

Dataset Information

Inhibition of indoleamine 2,3-dioxygenase 1 synergizes with oxaliplatin for efficient colorectal cancer therapy.

Publications

Inhibition of indoleamine 2,3-dioxygenase 1 synergizes with oxaliplatin for efficient colorectal cancer therapy.

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