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.

在评价抑制细胞生长的传统药物对小鼠的抗肿瘤作用的过程中， 中医，生芪方（由NCI的OCCAM计划支持的研究）， 由2种植物根（人参根和三七根（SQF））的水提取物组成， 注意到其对4 T1乳腺癌的抗肿瘤作用与显著的， 持续抑制外周MDSC。SQF抑制 IL-4R#61537;#61483;、Ly 6 G +/Gr 1+和CD 11b+细胞，以及IL-10， IL-1 #61538;#61484;#61472;脱氢酶和H2 O2产生。 SQF与吉西他滨联合使用可显著降低小鼠4 T1乳腺肿瘤的生长。 因此，MDSC的免疫抑制群体的减少促进了抗肿瘤作用。 健择。机制研究表明，肿瘤源性G-CSF和IL-1转移了肿瘤细胞的免疫功能， 未成熟DC和其他免疫细胞向MDSC样功能的成熟。作为MDSC 当它们浸润肿瘤时，它们成熟为促肿瘤替代活化免疫抑制剂 巨噬细胞（TAM）。对抗MDSC和TAM的方法在我们未来的计划中。它有 最近变得清楚的是，T细胞亚群例如CD 4 + CD 25 + FoxP 3 +T调节（Treg）细胞 是维持免疫稳态所必需的，并具有反馈抑制作用 对免疫反应的影响据报道，这些Treg细胞抑制自身免疫反应， 因此，不幸的是，也保护肿瘤免受免疫排斥。我们的研究 已经揭示了TNF通过作用于TNFR 2受体，其由TGF 1 α高度表达， 在小鼠中，它们的增殖扩增和功能激活都是意料之外的结果。 大多数肿瘤浸润性T细胞（TIL）实际上表达TNFR 2并被激活， 肿瘤源性TNF在外周淋巴细胞中的免疫抑制作用甚至比TGFAP更强， 组织中因此，我们的初步结果表明，抗TNF抑制小鼠生长 刘易斯肺和乳腺（4 T1）肿瘤。因此，通过确定更好的对抗Tibetan的手段，我们 可能能够增强对肿瘤疫苗的抗肿瘤反应。