德国癌症研究中心（DKFZ）Christiane A. Opitz课题组取得最新进展。他们发现IL4I1是一种代谢型免疫检查点，可激活活芳烃受体（AHR）并促进肿瘤进展。该成果于2020年8月19日发表在《细胞》杂志上。
色氨酸（Trp）分解代谢物激活AHR，可促进肿瘤恶性并抑制抗肿瘤免疫力。迄今为止，AHR靶基因的背景特异性阻碍了对AHR活性及其跨人类癌症上游酶的系统研究。通过自然语言处理得到的全组织AHR特征显示，在32个肿瘤实体中，白介素4诱导1（IL4I1）与IDR1或TDO2的结合比AID活性更频繁，迄今为止被认为是主要的Trp代谢酶。
IL4I1通过生成吲哚代谢产物和尿酸来激活AHR。它与神经胶质瘤患者的生存期缩短，促进癌细胞运动并抑制适应性免疫有关，从而增强了小鼠慢性淋巴细胞性白血病（CLL）的进程。免疫检查点封锁（ICB）诱导IDO1和IL4I1。由于IDO1抑制剂不会阻断IL4I1，因此IL4I1可能解释了ICB与IDO1抑制相结合的临床研究失败。
总之，IL4I1阻断剂为癌症治疗开辟了新途径。
附：英文原文
Title: IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression
Author: Ahmed Sadik, Luis F. Somarribas Patterson, Selcen ztürk, Soumya R. Mohapatra, Verena Panitz, Philipp F. Secker, Pauline Pfnder, Stefanie Loth, Heba Salem, Mirja Tamara Prentzell, Bianca Berdel, Murat Iskar, Erik Faessler, Friederike Reuter, Isabelle Kirst, Verena Kalter, Kathrin I. Foerster, Evelyn Jger, Carina Ramallo Guevara, Mansour Sobeh, Thomas Hielscher, Gernot Poschet, Annekathrin Reinhardt, Jessica C. Hassel, Marc Zapatka, Udo Hahn, Andreas von Deimling, Carsten Hopf, Rita Schlichting, Beate I. Escher, Jürgen Burhenne, Walter E. Haefeli, Naveed Ishaque, Alexander Bhme, Sascha Schuble, Kathrin Thedieck, Saskia Trump, Martina Seiffert, Christiane A. Opitz
Issue&Volume:
Abstract: Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhancestumor malignancy and suppresses anti-tumor immunity. The context specificity of AHRtarget genes has so far impeded systematic investigation of AHR activity and its upstreamenzymes across human cancers. A pan-tissue AHR signature, derived by natural languageprocessing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR throughthe generation of indole metabolites and kynurenic acid. It associates with reducedsurvival in glioma patients, promotes cancer cell motility, and suppresses adaptiveimmunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL)in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinicalstudies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens newavenues for cancer therapy.
DOI: 10.1016/j.cell.2020.07.038
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30946-6