Role of T regulatory suppression in autoimmunity and cancer

T 调节抑制在自身免疫和癌症中的作用

• 批准号: 7965551
• 负责人: JOOST J OPPENHEIM
• 金额: $ 41.26万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965551
• 关键词: Antitumor Response; Autoimmune Responses; Autoimmunity; Breast; CSF3 gene; Cancer Vaccines; Cells; Chinese Traditional Medicine; Cytostatics; Feedback; Future; Growth; Homeostasis; Hydrogen Peroxide; ITGAM gene; Immune; Immune response; Immunosuppressive Agents; Interleukin-1; Interleukin-10; Lung; Lymphoid Tissue; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mus; Panax; Peripheral; Plant Roots; Population; Production; Qi; Reporting; Role; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; TNFRSF1B gene; Talus; Tumor-Derived; Water; arginase; gemcitabine; macrophage; malignant breast neoplasm; man; programs; receptor; tumor

In the course of evaluating the antitumor effects in mice of a cytostatic traditional Chinese Medicine, Sheng Qi Formula (studies supported by the OCCAM program of the NCI), consisting of a water extract of 2 plant roots (Radx Astragali and Panax Notoginsenga (SQF), it was noted that its antitumor effect on 4T1 breast cancer was associated with marked and consistent suppression of peripheral MDSC. SQF inhibited IL-4R, Ly6G+/Gr1+, and CD11b+ cells, as well as IL-10, IL-1arginase and H2O2 production. In combination with gemcitabine, SQF markedly reduced the growth of 4T1 breast tumor in mice. Thus, reduction in the immunosuppressive populations of MDSC promoted the antitumor effect of gemcitabine. Studies of the mechanism suggest that tumor derived G-CSF and IL-1 divert the maturation of immature DC and other immune cells toward MDSC-like functions. As MDSC infiltrate tumors, they mature into tumor-promoting alternatively activated immunosuppressive macrophages (TAM's). Means of counteracting MDSC's and TAM's are in our future plans. It has recently become clear that a subset of T cells e.g. CD4+CD25+FoxP3+T regulatory (Treg) cells are essential in the maintenance of immune homeostasis and have feedback suppressive effects on immune responses. These Treg cells have been reported to suppress autoimmune responses and consequently, unfortunately, also protect tumors from immune rejection. Our studies of Tregs have revealed that TNF by acting on the TNFR2 receptor, which is highly expressed by Tregs, unexpectantly results in their proliferative expansion and functional activation both in mice and in man. Most tumor infiltrating T cells (TIL's) actually express TNFR2 and are activated by tumor-derived TNF to be even more immunosuppressive than Tregs in peripheral lymphoid tissues. Consequently, our preliminary results show that anti-TNF reduced the growth of mouse Lewis lung and breast (4T1) tumors. Thus, by identifying better means of countering Tregs, we may be able to enhance antitumor responses to tumor vaccines.

在评估中静态传统药物的抗肿瘤作用的过程中，Sheng Qi配方奶粉（由NCI的OCCAM计划支持），由2种植物根（Radx Astragali和Panax notoginsenga（sqf））组成，其抗抑制作用与4T1乳腺癌相关，并且与MARKS CANSENT相关，并且是对抗抑制作用的效果。 SQF抑制了IL-4R＆＃61537;＆＃61483;＆＃61483; ly6g+/gr1+，CD11b+细胞以及IL-10，IL-1＆＃61538;＆＃61484;＆＃61484;＆＃61472;＆＃61472; and-＆＃61472; Arginase and H2O2与H2O2的生产相结合。因此，MDSC的免疫抑制种群的减少促进了吉西他次的抗肿瘤作用。 （tam的）。抵消MDSC和TAM的手段是我们未来的计划。最近很明显，T细胞的一部分，例如CD4+CD25+FOXP3+T调节性（TREG）细胞对于维持免疫稳态至关重要，并且对免疫反应具有反馈抑制作用。据报道，这些Treg细胞抑制自身免疫反应，因此不幸的是，还可以保护肿瘤免疫排斥。我们对Tregs的研究表明，TNF通过对TNFR2受体作用，该受体高度表达了Tregs，因此，在小鼠和人类中，它们都导致了它们的增殖膨胀和功能激活。大多数肿瘤浸润的T细胞（TIL）实际上表达了TNFR2，并被肿瘤衍生的TNF激活，比外周淋巴组织中的Tregs更为免疫抑制。因此，我们的初步结果表明，抗TNF减少了小鼠刘易斯肺和乳腺（4T1）肿瘤的生长。因此，通过确定更好的Treg手段，我们可能能够增强对肿瘤疫苗的抗肿瘤反应。