Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer.
Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer.
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DOI：
10.3389/fonc.2018.00370
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发表时间：
2018
影响因子：
4.7
通讯作者：
Prendergast GC
中科院分区：
文献类型：
--
作者：
Fox E;Oliver T;Rowe M;Thomas S;Zakharia Y;Gilman PB;Muller AJ;Prendergast GC
在很大程度上，对IDO/TDO酶介导的色氨酸分解代谢的研究推动了人们对免疫代谢作为新癌症治疗方法来源的兴趣激增。该领域的主要焦点是IDO1，这是一种促炎调节剂，在癌症中广泛过度表达，使免疫监视变迟钝，使新血管形成和转移。简单的外消旋化合物1-甲基- d， l-色氨酸（1MT）是IDO/TDO途径广泛使用的探针，具有多种复杂的抑制作用。1MT的L异构体是IDO1的弱底物，并归因于外消旋体对酶的弱抑制活性。相反，D异构体既不结合也不抑制纯化的IDO1酶。然而，临床开发主要集中在D-1MT（现在称为indoximod），因为临床前提示其具有更强的抗癌活性和独特的作用机制。与IDO1的直接酶抑制剂相比，吲哚肟模作用于IDO1的下游，刺激所有IDO/TDO酶的趋同效应信号分子mTORC1，从而可能降低IDO1旁路的耐药风险。在这篇综述中，我们调查了indoximod作为IDO/TDO途径抑制剂的独特生物学和机制特征，包括最近的临床发现，它能够安全地增强各种类型的癌症治疗，包括化疗、化疗放疗、疫苗和免疫检查点治疗。我们还回顾了与选择性ido1特异性阻断相比，吲哚mod提供的潜在优势，临床前研究和临床研究ECHO-301表明，选择性ido1特异性阻断可能很容易被肿瘤绕过。Indoximod处于广谱免疫代谢药物的前沿，可以改善对许多抗癌方式的反应，其方式类似于在传染病环境中增强免疫力的疫苗佐剂。
Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.
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影响因子：
8.8
作者：
Holmgaard RB;Zamarin D;Li Y;Gasmi B;Munn DH;Allison JP;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
4.4
作者：
D Basu, Gargi;Tinder, Teresa L.;Mukherjee, Pinku
通讯作者：
Mukherjee, Pinku
影响因子：
11.2
作者：
Hou, De-Yan;Muller, Alexander J.;Munn, David H.
通讯作者：
Munn, David H.
影响因子：
11.2
作者：
Fu, Tihui;He, Qiuming;Sharma, Padmanee
通讯作者：
Sharma, Padmanee
影响因子：
10.1
作者：
Hennequart, Marc;Pilotte, Luc;van den Eynde, Benio T. J.
通讯作者：
van den Eynde, Benio T. J.