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      Feiji Recipe Reverses Lung Cancer Immune Escape by Inhibiting the Expression of IDO

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          Abstract

          Tumor cells have developed multiple mechanisms to escape immune recognition mediated by T cells. Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme inducing immune tolerance, is involved in tumor escape from host immune systems. Feiji Recipe, a Chinese herbal recipe that composed of 12 traditional Chinese medicines, has been used to recover immuno-surveillance and to interven immune escape in lung cancer patients. To elucidate the biological role of IDO in the tumorigenesis of lung cancer, and the intervention of Feiji Recipe on tumor immune escape, we established a mouse lung cancer cell line (2LL-EGFP-IDO) with overexpression of IDO. IDO expression did not affect cell proliferation. 2LL-EGFP-IDO cells were effective in reducing the level of tryptophan and increasing the level of its downstream metabolites, kynurenines, in culture medium as assessed by HPLC. Feiji Recipe could up-regulate the percentage of CD8+ T cells by inhibits the expression of IDO in co-culture system. The results of these studies indicate that Feiji Recipe can enhance the immune response and reverses tumor immune escape by induce the activity of CD8+ T cells, which might be related to the inhibition of IDO expression.

          Translated abstract

          肿瘤细胞能够通过多种机制逃避T细胞介导的免疫识别,而吲哚胺2,3-双加氧酶(IDO)是一种色氨酸代谢酶,它能够通过降解色氨酸,同时产生犬尿氨酸,从而诱导免疫耐受,最终导致肿瘤细胞逃避宿主免疫杀伤。肺积方是由12位中药组成的复方,已被证实能够干预免疫逃逸,提高肺癌患者的免疫监视能力。为进一步探讨IDO在肺癌的发生发展过程中的生物学作用和肺积方对肿瘤免疫逃逸的干预机制,本研究构建了过表达IDO的小鼠肺癌细胞株(2LL-EGFP-IDO)。IDO的过表达不影响2LL细胞的增殖。高效液相检测结果显示2LL-EGFP-IDO细胞能够有效的代谢培养基中的色氨酸,同时产生其下游代谢产物犬尿氨酸。而共培养体系中,肺积方干预后能够抑制IDO的表达,从而上调CD8+ T细胞的比例。我们的研究表明肺积方能够通过抑制IDO的表达,上调CD8+ T细胞的比例,以增强免疫应答、逆转肿瘤细胞的免疫逃逸。

          Most cited references20

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          Cancer statistics, 2014.

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data were collected by the National Center for Health Statistics. A total of 1,665,540 new cancer cases and 585,720 cancer deaths are projected to occur in the United States in 2014. During the most recent 5 years for which there are data (2006-2010), delay-adjusted cancer incidence rates declined slightly in men (by 0.6% per year) and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.4% per year in women. The combined cancer death rate (deaths per 100,000 population) has been continuously declining for 2 decades, from a peak of 215.1 in 1991 to 171.8 in 2010. This 20% decline translates to the avoidance of approximately 1,340,400 cancer deaths (952,700 among men and 387,700 among women) during this time period. The magnitude of the decline in cancer death rates from 1991 to 2010 varies substantially by age, race, and sex, ranging from no decline among white women aged 80 years and older to a 55% decline among black men aged 40 years to 49 years. Notably, black men experienced the largest drop within every 10-year age group. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population. © 2014 American Cancer Society, Inc.
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            IDO expression by dendritic cells: tolerance and tryptophan catabolism.

            Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.
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              Imatinib potentiates anti-tumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido

              Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and achieves a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the anti-tumor effects of imatinib. Imatinib therapy activated CD8+ T cells and induced regulatory T cell (T reg) apoptosis within the tumor by reducing tumor cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are critical to the anti-tumor effects of imatinib in GIST and concomitant immunotherapy may further improve outcome in human cancers treated with targeted agents.
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                Author and article information

                Contributors
                Journal
                Traditional Medicine Research
                Traditional Medicine Research
                TMR Editorial Board (Jintang road, 99, Hedong district Tianjin,China, 300170. )
                2413-3973
                January 2016
                5 January 2016
                : 1
                : 3
                : 149-155
                Affiliations
                [1-2413-3973-1-3-149] 1Department of Hematology and Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
                [2-2413-3973-1-3-149] 2Longhua Hospital, Shanghai University of Traditional Chinese Medicine, National Clinical Research Centre for Traditional Chinese Medicine and Oncology, 725 South Wanping Rd, Shanghai 200032, China
                [3-2413-3973-1-3-149] 3State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China, University of Science and Technology, #268, 130 Meilong Rd, Shanghai, 200237, China
                Author notes
                Corresponding to: Jian-Hui Tian, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, National Clinical Research Centre for Traditional Chinese Medicine and Oncology, 725 South Wanping Rd., Shanghai 200032, China, E-mail: hawk7150@ 123456hotmail.com He-Gen Li, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, National Clinical Research Centre for Traditional Chinese Medicine and Oncology, 725 South Wanping Rd., Shanghai 200032, China, E-mail: shlaogen@ 123456163.com
                Submitted: 15 May 2016

                Executive Editor: Cui-Hong Zhu English Editor: Jian Hao

                Article
                2413-3973-1-3-149
                890b4839-162c-4c5d-b6d6-d2f2421e6f78

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 14 June 2016
                Categories
                Orginal Article
                Medicine
                Traditional Medicine

                Medicine,Pharmacology & Pharmaceutical medicine,Health & Social care,Complementary & Alternative medicine
                Feiji Recipe,3-dioxygenase (IDO),Indoleamine 2,Non-small cell lung cancer,IDO+ mouse Lewis lung cancer cell line,Immune escape

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