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.

在评估细胞抑制中药生气方（NCI OCCAM 项目支持的研究）对小鼠的抗肿瘤作用过程中，生气方由 2 种植物根（黄芪和三七 (SQF)）的水提取物组成，注意到其对 4T1 乳腺癌的抗肿瘤作用与显着且持续的外周 MDSC 抑制有关。 SQF 抑制 IL-4R、Ly6G+/Gr1+ 和 CD11b+ 细胞，以及 IL-10、IL-1精氨酸酶和 H2O2 的产生。 与吉西他滨联合使用，SQF 显着减少了 4T1 乳腺肿瘤的生长 老鼠。 因此，MDSC免疫抑制群体的减少促进了吉西他滨的抗肿瘤作用。该机制的研究表明，肿瘤来源的 G-CSF 和 IL-1 将未成熟 DC 和其他免疫细胞的成熟转向 MDSC 样功能。当 MDSC 浸润肿瘤时，它们会成熟为促进肿瘤的替代激活的免疫抑制巨噬细胞 （TAM 的）。对抗 MDSC 和 TAM 的方法已在我们未来的计划中。最近已经清楚，T 细胞的一个子集，例如CD4+CD25+FoxP3+T 调节 (Treg) 细胞对于维持免疫稳态至关重要，并对免疫反应具有反馈抑制作用。据报道，这些 Treg 细胞可以抑制自身免疫反应，因此，不幸的是，它们还可以保护肿瘤免受免疫反应的影响。 拒绝。我们对 Tregs 的研究表明，TNF 通过作用于 Tregs 高度表达的 TNFR2 受体，出人意料地导致小鼠和人类的增殖扩张和功能激活。大多数肿瘤浸润 T 细胞 (TIL) 实际上表达 TNFR2，并被肿瘤源性 TNF 激活，比外周血中的 Tregs 具有更强的免疫抑制作用 淋巴组织。因此，我们的初步结果表明，抗 TNF 药物减少了小鼠 Lewis 肺和乳腺 (4T1) 肿瘤的生长。因此，通过找到更好的对抗 Tregs 的方法，我们或许能够增强对肿瘤疫苗的抗肿瘤反应。