Regulation of T cell Functions by the Breast Cancer Microenvironment

乳腺癌微环境对 T 细胞功能的调节

• 批准号: 7727392
• 负责人: MATTHEW F KRUMMEL
• 金额: $ 36.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727392
• 关键词: Ablation; Address; Adoption; Antigens; Biological Models; Bolus Infusion; CD4 Positive T Lymphocytes; CD8B1 gene; Carcinoma; Cell Count; Cell physiology; Cells; Collecting Cell; Data; Development; Etiology; Failure; Feedback; Flow Cytometry; Fluorescence; Human; Hyperplasia; Imagery; Immune; Immune response; Immune system; Immunologic Surveillance; Light; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Microscopy; Modeling; Mus; Nature; Neoplasm Metastasis; Phenotype; Photons; Population; Primary Neoplasm; Regulation; Role; Sampling; System; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tumor Antigens; adenoma; base; cell motility; cell type; human disease; in vitro Assay; in vivo; lymph nodes; macrophage; malignant breast neoplasm; neoplastic cell; prevent; research study; response; tumor; tumor growth

Why don't tumor-reactive T cells eliminate tumors? Although priming in the draining lymph node is often suboptimal, more frequently, the immune response is stymied at the tumor itself. This may be as a result of a protection of the tumor from immune surveillance (tolerance) or inadequate repriming and feedback to the local draining lymph node (an interrupted feedback loop). Based on a panel of preliminary data, we hypothesize that a subpopulation of APCs in the tumor microenvironment protect the tumor from CTLs by direct interaction with the T cells, by their failure to mature in response to the interaction, and by cooperation with regulatory T cells. We believe the microenvironment builds an arsenal of these cells and collects the immune system at 'inactivating foci' that prevent stable and effective surveillance of the tumor by primed CTLs. By simultaneously preventing the I cells from seeing the tumor and suboptimally activating them there, these cells may effectively neutralize the response. We propose to study this in a new model system of human breast cancer, the PyMTCherry-OVA mouse that we have produced and characterized expressly to address this poorly accessible problem. The model allows direct visualization of the tumor AND the tumor-sampling APCs via intrinsic fluorescence. This is significant as we are able to study what is happening to the T cell as it contacts these distinct cell types, specifically via 2-photon microscopy. It is also significant because we are also able to phenotype this very important APC population using multicolor flow cytometry, microarray, and in vitro assays and provide key data about the co-development of APC and I cell population that results in tumor acceptance. It should be noted that the studies proposed are amongst the first of their kind that will be achievable in a non-ectopic tumor model that very closely resemble human breast cancer in many important ways. The spontaneous eteliology of our model is also important, as there are many reasons that ectopic tumors are unlikely to faithfully replicate important aspects of immune-evasion, including the microenvironment, by a primary tumor. Thus, studies in this system are much more likely to recapitulate the features of human disease and the 'normal' establishment of immune evasion. The results of these experiments are going to reveal the dynamics of I cells over time in the developing hyperplasia through to established carcinomas. They will also definitely reveal the interaction of regulatory I cells with cells of the local I cell response. Finally, and not insignificantly, they will shed considerable light upon a previously inaccessible cell population which may protect the tumor from the immune response and thus permit tumor growth and metastasis.

为什么肿瘤反应性T细胞不消除肿瘤？尽管在排水淋巴结中的启动通常是次优的，但更频繁地，免疫反应在肿瘤本身上受阻。这可能是由于保护肿瘤免受免疫监测（耐受性）的保护或对局部排水淋巴结（中断反馈循环）的谴责和反馈不足的结果。 基于一系列初步数据，我们假设通过与T细胞直接相互作用，通过与T细胞直接相互作用，通过与调节性T细胞的合作，通过与T细胞直接相互作用，通过与T细胞直接相互作用，通过与T细胞直接相互作用来保护肿瘤免受CTL的影响。我们认为，微环境可以建立这些细胞的武器库，并以“失活灶”收集免疫系统，以防止启动的CTL对肿瘤进行稳定和有效的监测。通过同时防止I细胞看到肿瘤并在那里次优地激活它们，这些细胞可能有效地 中和响应。 我们建议在一种新的人类乳腺癌模型系统中研究这一点，即我们已经产生并明确特征的Pymtcherry-ova小鼠，以解决这个易于接近的问题。该模型允许通过内在荧光直接可视化肿瘤和肿瘤采样APC。这很重要，因为我们能够研究T细胞正在发生的事情，因为它与这些不同的细胞类型（特别是通过2光子显微镜）接触。这也很重要，因为我们还能够使用多色流式细胞仪，微阵列和体外测定法表现出非常重要的APC种群，并提供有关APC和I细胞群体共生的关键数据，从而导致肿瘤接受。 应当指出的是，提出的研究是在非调节性肿瘤模型中可以实现的第一个研究，这些模型在许多重要方面都非常类似于人类乳腺癌。我们模型的自发性播放学也很重要，因为有很多原因表明异位肿瘤不太可能忠实地复制原发性肿瘤在内的免疫异常（包括微环境）的重要方面。 因此，该系统中的研究更有可能概括人类疾病的特征和“正常”的免疫逃避。这些实验的结果将揭示I细胞在发育中的增生到已建立的癌的动力学。它们也肯定会揭示调节I细胞与局部I细胞反应的细胞的相互作用。最后，并不是微不足道的，他们将对以前无法接近的细胞种群进行大量揭示，该细胞种群可能保护肿瘤免受免疫反应的影响，从而允许肿瘤生长和转移。