Treg-Th17 Axis Modulation and Induction of Tumor Immunity with Cryosurgery

通过冷冻手术调节 Treg-Th17 轴并诱导肿瘤免疫

• 批准号: 8197978
• 负责人: Jesse James Veenstra
• 金额: $ 3.63万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197978
• 关键词: Ablation; Advanced Malignant Neoplasm; Affect; Aging; Antigens; Biological Assay; Blood Vessels; Breast Cancer Treatment; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Death; Cell membrane; Cell physiology; Cells; Chemotherapy-Oncologic Procedure; Clinical; Cold Therapy; Cosmetics; Cross Presentation; Cryosurgery; Cytotoxic T-Lymphocytes; DNA; DNA Vaccines; Data; Dendritic Cell Vaccine; Dendritic Cells; Disease; Distant; ERBB2 gene; Environment; Enzyme-Linked Immunosorbent Assay; Equilibrium; Excision; Flow Cytometry; Freezing; Generations; Goals; Immune; Immune response; Immune system; Immunization; Immunologics; Immunosuppression; Inbred BALB C Mice; Inflammatory; Injection of therapeutic agent; Interleukin-17; Interleukin-6; Intervention; Kidney; Kinetics; Liver; Lymph; Malignant Neoplasms; Measures; Memory; Methods; Modality; Modeling; Monitor; Mus; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Organelles; Outcome; Patients; Phenotype; Population; Procedures; Prostate; Recurrence; Regimen; Regulatory T-Lymphocyte; Role; Self Tolerance; Serum; Skin; Solid Neoplasm; Spleen; Stress; Structure; System; T cell response; T-Cell Activation; T-Lymphocyte; Temperature; Testing; Thrombosis; Time; TimeLine; Tissues; Transgenic Organisms; Tumor Antigens; Tumor Immunity; Vaccinated; Vaccination; aged; aggressive therapy; aging population; analog; base; cancer therapy; cell motility; cytokine; enzyme linked immunospot assay; immunoregulation; improved; interest; lymph nodes; minimally invasive; neoplastic cell; novel; patient population; peripheral blood; prevent; public health relevance; research study; response; tumor; tumor growth

DESCRIPTION (provided by applicant): Cancer is a difficult disease to treat due to its destructive nature. This is especially true in the aging population, where patients cannot tolerate more aggressive therapies, such as invasive surgery and chemotherapy regimens. Alternatively, cryosurgery, the use of freezing temperatures to destroy diseased tissue, is increasingly recognized as an efficient, minimally invasive method of treating solid tumors. Compared to surgical resection, cryosurgery is less damaging to surrounding structures, places less stress on the body, has improved patient comfort, is more affordable, and provides a better cosmetic result. More importantly, cryosurgery has the potential to induce an immunologic response to tumor-associated antigens, which are released from the ablated tumor. Not only is this immune response able to prevent tumor recurrence in patients but it is also capable of eliminating distant metastatic foci. However the mechanisms by which cryoablation induces anti-tumor immunity have yet to be elucidated. The goal of this project is to resolve these mechanisms by studying the interaction between the immune regulatory system and cryoablation. This project will focus on the immune inhibitory (T regulatory cells) and pro-inflammatory (Th17 cells) axis that exists within the immune system. This axis can be shifted from one spectrum to the other creating a variety of immune inhibitory or stimulatory environments. Our preliminary data have shown that cryoablation increases both T regulatory (Treg) and Th17 populations, indicating that the Treg-Th17 axis has a significant role after cryosurgery. We hypothesize that a shift in this axis towards the pro-inflammatory spectrum (Th17 cells) will allow immune effectors to overcome self tolerance and induce long term anti-tumor immunity. To test this hypothesis we propose the following aims: 1) Characterize the kinetics of T-cell activation and cytokine profiles in mice after cryosurgery to determine the shifts in the Treg-Th17 axis, 2) Alter the mouse immune environment to favor Th17 response in coordination with cryosurgery, and 3) Evaluate anti-tumor activity when DNA vaccination and cryosurgery are combined. PUBLIC HEALTH RELEVANCE: The goal is to eliminate the solid tumor mass by cryosurgery and release all tumor-associated antigens to boost anti-tumor immune response. A less invasive procedure, cryosurgery may be advantageous for senior patients who are not able to endure harsh treatment options. To facilitate the activation of effectors, rather than suppressive T cells following cryotherapy, I will test the hypothesis that inducing a shift from the regulatory T cells toward IL-17 producing T cells before cryosurgery by intratumoral expression of IL-6 will favor anti-tumor immune response. Furthermore, systemic immunization with DNA vaccine will be tested to compliment cryosurgery. Results from this study could significantly advance cancer treatment, especially in senior patients.

描述（由申请人提供）：由于其破坏性，癌症是一种难以治疗的疾病。这在老龄化人群中尤其如此，患者不能耐受更积极的治疗，如侵入性手术和化疗方案。或者，冷冻手术，使用冷冻温度来破坏患病组织，越来越被认为是治疗实体瘤的有效，微创方法。与手术切除相比，冷冻手术对周围结构的损伤较小，对身体的压力较小，改善了患者的舒适度，价格更实惠，并提供了更好的美容效果。更重要的是，冷冻手术有可能诱导对肿瘤相关抗原的免疫反应，这些抗原是从消融的肿瘤中释放出来的。这种免疫应答不仅能够预防患者的肿瘤复发，而且还能够消除远处转移灶。然而，冷冻消融诱导抗肿瘤免疫的机制尚未阐明。本项目的目标是通过研究免疫调节系统和冷冻消融之间的相互作用来解决这些机制。该项目将重点关注免疫系统中存在的免疫抑制（T调节细胞）和促炎（Th 17细胞）轴。该轴可以从一个光谱移动到另一个光谱，从而产生各种免疫抑制或刺激环境。我们的初步数据表明，冷冻消融增加了调节性T细胞（Treg）和Th 17细胞群，表明Treg-Th 17轴在冷冻手术后具有重要作用。我们假设，该轴向促炎谱（Th 17细胞）的转变将允许免疫效应物克服自身耐受并诱导长期抗肿瘤免疫。为了验证这一假设，我们提出了以下目标：1）表征冷冻手术后小鼠中T细胞活化和细胞因子谱的动力学，以确定Treg-Th 17轴的变化，2）改变小鼠免疫环境以有利于与冷冻手术协调的Th 17应答，以及3）当DNA疫苗接种和冷冻手术组合时评估抗肿瘤活性。 公共卫生关系：目的是通过冷冻手术消除实体瘤块，释放所有肿瘤相关抗原，以增强抗肿瘤免疫反应。冷冻手术是一种侵入性较小的手术，对于无法忍受苛刻治疗选择的老年患者可能是有利的。为了促进效应物的激活，而不是冷冻治疗后的抑制性T细胞，我将检验以下假设：在冷冻手术前通过肿瘤内表达IL-6诱导从调节性T细胞向产生IL-17的T细胞的转变将有利于抗肿瘤免疫应答。此外，将测试DNA疫苗的全身免疫以补充冷冻手术。这项研究的结果可以显着推进癌症治疗，特别是老年患者。