Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer.
Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer.
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DOI：
10.1158/1078-0432.ccr-09-3272
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发表时间：
2010-03-15
期刊：
影响因子：
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通讯作者：
Gabrilovich DI
中科院分区：
文献类型：
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作者：
Nagaraj S;Youn JI;Weber H;Iclozan C;Lu L;Cotter MJ;Meyer C;Becerra CR;Fishman M;Antonia S;Sporn MB;Liby KT;Rawal B;Lee JH;Gabrilovich DI
髓源性抑制细胞(MDSC)是肿瘤免疫抑制的主要因素之一。因此，确定有效的治疗手段来调节这些细胞将是重要的。我们评价了合成的2-氰基-3，12-二氧乙烯-1，9-二烯-28-酸三萜类C-28甲酯(CDDO-Me；巴度松甲基)对MC38结肠癌、Lewis肺癌和EL-4胸腺瘤小鼠肿瘤模型以及肾细胞癌和软组织肉瘤患者血液标本的作用。还对接受CDDO-Me联合吉西他滨治疗的胰腺癌患者的样本进行了分析。在体外，浓度为25-100 nM的CDDO-Me可完全消除MDSC的免疫抑制活性。CDDO-Me可减少MDSC中的活性氧，但不影响其活性或一氧化氮和精氨酸酶的水平。CDDO-Me治疗荷瘤小鼠不影响脾中MDSC的比例，但消除了它们的抑制活性。这种作用与抗肿瘤活性无关。CDDO-Me治疗可降低小鼠肿瘤生长。对免疫缺陷的SCID-米色小鼠的实验表明，这种影响在很大程度上是由免疫系统介导的。CDDO-Me显著增强了一种肿瘤疫苗的抗肿瘤效果。CDDO-Me治疗胰腺癌患者不影响外周血中MDSC的数量，但显着提高免疫应答。CDDO-Me消除了MDSC的免疫抑制作用，并改善了荷瘤小鼠和癌症患者的免疫反应。它可能通过增强癌症免疫治疗的效果而代表一种有吸引力的治疗选择。
Myeloid-derived suppressor cells (MDSC) are one of the major factors responsible for immune suppression in cancer. Therefore it would be important to identify effective therapeutic means to modulate these cells. We evaluated the effect of the synthetic triterpenoid C-28 methyl ester of 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO-Me; bardoxolone methyl) in MC38 colon carcinoma, Lewis lung carcinoma, and EL-4 thymoma mouse tumor models as well as blood samples from patients with renal cell cancer and soft tissue sarcoma. Samples were also analyzed from patients with pancreatic cancer treated with CDDO-Me in combination with gemcitabine. CDDO-Me at concentrations of 25-100 nM completely abrogated immune suppressive activity of MDSC in vitro. CDDO-Me reduced reactive oxygen species in MDSC but did not affect their viability or the levels of nitric oxide and arginase. Treatment of tumor-bearing mice with CDDO-Me did not affect the proportion of MDSC in the spleens but eliminated their suppressive activity. This effect was independent of antitumor activity. CDDO-Me treatment decreased tumor growth in mice. Experiments with immune-deficient SCID-beige mice indicated that this effect was largely mediated by the immune system. CDDO-Me substantially enhanced the antitumor effect of a cancer vaccines. Treatment of pancreatic cancer patients with CDDO-Me did not affect the number of MDSC in peripheral blood but significantly improved the immune response. CDDO-Me abrogated the immune suppressive effect of MDSC and improved immune responses in tumor-bearing mice and cancer patients. It may represent an attractive therapeutic option by enhancing the effect of cancer immunotherapy.