CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Targeting Tryptophan Catabolism in Ovarian Cancer to Attenuate Macrophage Infiltration and PD-L1 Expression.
Targeting Tryptophan Catabolism in Ovarian Cancer to Attenuate Macrophage Infiltration and PD-L1 Expression.
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高级别浆液性癌（HGSC）是输卵管、卵巢和腹膜最常见的卵巢癌类型，由于TIL（肿瘤浸润淋巴细胞）的存在可带来更好的预后，因此被认为具有免疫原性。然而，由于免疫抑制性肿瘤微环境（TME），免疫治疗的疗效一直有限。肿瘤代谢和免疫抑制性代谢物通过消耗营养物质和激活免疫抑制性转录程序，直接影响免疫细胞功能。色氨酸（TRP）分解代谢是HGSC疾病进展的一个促进因素。两种结构上不同的限速TRP分解代谢酶——吲哚胺2,3-双加氧酶1（IDO1）和色氨酸2,3-双加氧酶2（TDO2）——分别独立进化以分解代谢TRP。IDO1/TDO2在癌中异常表达，并将TRP代谢为免疫抑制性代谢物犬尿氨酸（KYN），后者可结合芳香烃受体以驱动免疫抑制性转录程序。迄今为止，临床试验中测试的IDO抑制剂疗效有限，但这些抑制剂并未靶向TDO2，而我们发现HGSC细胞系和临床结局对TDO2的依赖程度高于IDO1。为了识别预后不良的炎症性HGSC癌症，我们按IL6状态对患者腹水样本进行了分层，IL6状态与不良预后相关。代谢组学显示，IL6高的患者样本中KYN富集。TDO2敲低显著抑制了HGSC生长和TRP分解代谢。口服可用的IDO1/TDO2双重抑制剂AT-0174显著抑制了肿瘤进展，减少了肿瘤相关巨噬细胞，并降低了免疫细胞和肿瘤细胞上免疫抑制性蛋白的表达。这些研究表明了TDO2的重要性以及AT-0174克服免疫抑制性TME的治疗潜力。意义：开发改善化疗反应的策略对于延长输卵管、卵巢和腹膜HGSC患者的无病间期至关重要。在本文中，我们证明靶向TRP分解代谢，特别是通过TDO2和IDO1的双重抑制，可减弱免疫抑制性微环境，并且与化疗联合使用时，与单独化疗相比可延长生存期。
UNLABELLED: High-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic because the presence of tumor-infiltrating lymphocytes conveys a better prognosis.
However, the efficacy of immunotherapies has been limited because of the immune-suppressed tumor microenvironment (TME). Tumor metabolism and immune-suppressive metabolites directly affect immune cell function through the depletion of nutrients and activation of immune-suppressive transcriptional programs. Tryptophan (TRP) catabolism is a contributor to HGSC disease progression. Two structurally distinct rate-limiting TRP catabolizing enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2), evolved separately to catabolize TRP. IDO1/TDO2 are aberrantly expressed in carcinomas and metabolize TRP into the immune-suppressive metabolite kynurenine (KYN), which can engage the aryl hydrocarbon receptor to drive immunosuppressive transcriptional programs. To date, IDO inhibitors tested in clinical trials have had limited efficacy, but those inhibitors did not target TDO2, and we find that HGSC cell lines and clinical outcomes are more dependent on TDO2 than IDO1.
To identify inflammatory HGSC cancers with poor prognosis, we stratified patient ascites samples by IL6 status, which correlates with poor prognosis. Metabolomics revealed that IL6-high patient samples had enriched KYN. TDO2 knockdown significantly inhibited HGSC growth and TRP catabolism. The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells.
These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME. SIGNIFICANCE: Developing strategies to improve response to chemotherapy is essential to extending disease-free intervals for patients with HGSC of the fallopian tube, ovary, and peritoneum.
In this article, we demonstrate that targeting TRP catabolism, particularly with dual inhibition of TDO2 and IDO1, attenuates the immune-suppressive microenvironment and, when combined with chemotherapy, extends survival compared with chemotherapy alone.
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