PDF(Pubmed)
Abstract：
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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
输卵管高级别浆液性癌（HGSC），卵巢和腹膜是最常见的卵巢癌类型，并且由于肿瘤浸润淋巴细胞的存在具有更好的预后，因此预计具有免疫原性。然而,由于免疫抑制的肿瘤微环境(TME),免疫疗法的疗效受到限制.肿瘤代谢和免疫抑制代谢物通过营养物质的消耗和免疫抑制转录程序的激活直接影响免疫细胞功能。色氨酸(TRP)分解代谢是HGSC疾病进展的贡献者。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代谢为免疫抑制代谢物犬尿氨酸（KYN），它可以参与芳香烃受体（AhR）来驱动免疫抑制转录程序。迄今为止,在临床试验中测试的IDO抑制剂的疗效有限，但这些抑制剂并不靶向TDO2,我们发现HGSC细胞系和临床结局比IDO1更依赖于TDO2.为了确定预后不良的炎性HGSC癌症，我们通过IL6状态对患者腹水样本进行分层，这与预后不良有关。代谢组学显示，高IL6患者样品富集了KYN。TDO2敲低显著抑制HGSC生长和TRP分解代谢。口服可用的双重IDO1/TDO2抑制剂，AT-0174，显著抑制肿瘤进展，减少肿瘤相关巨噬细胞，免疫细胞和肿瘤细胞上免疫抑制蛋白的表达减少。这些研究证明了TDO2的重要性和AT-0174克服免疫抑制的TME的治疗潜力。
