Comparing the Impact of Cold Stress on Anti-tumor Immunity in Young and Aged Mice

比较冷应激对年轻和老年小鼠抗肿瘤免疫的影响

• 批准号: 8809734
• 负责人: ELIZABETH A REPASKY
• 金额: $ 8.58万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8809734
• 关键词: Address; Adrenergic Agents; Aging; CD8B1 gene; Cancer Immunology Science; Cancer Patient; Carcinogens; Cells; Chronic; Data; Development; Effector Cell; Elderly; Equilibrium; Face; Frequencies; Future; Goals; Growth; House mice; Housing; Human; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Impairment; Individual; Inflammatory; Intervention; Laboratories; Lead; Learning; Malignant Neoplasms; Modeling; Mouse Strains; Mus; Neoplasm Metastasis; Outcome; Physiologic Thermoregulation; Physiological; Pilot Projects; Production; Reagent; Research; Research Institute; Research Personnel; Signal Pathway; Spleen; Stress; T-Lymphocyte; Temperature; Testing; Time; Toxic effect; Tumor Immunity; Vaccines; Work; adrenergic; aged; anti aging; chemokine; comparative; cytokine; experience; impression; improved; juvenile animal; lymph nodes; macrophage; mouse model; novel; older patient; preclinical study; preference; public health relevance; research clinical testing; research facility; research study; response; thermal stress; tumor; tumor growth; tumor microenvironment; tumorigenic

DESCRIPTION (provided by applicant): Mouse models are used heavily in aging research and the results of these experiments are used to predict differences in anti-tumor immunity and efficacy of immunotherapy between young and aged humans. Recent work from our laboratory has demonstrated that thermoregulatory challenges arising from cool housing conditions mandated for mouse research colonies have had an unrecognized impact on our attempts to understand the anti-tumor capabilities of the immune response of young mice, particularly the balance between anti-tumor effector cells and pro-tumorigenic immunosuppressive cells. Interestingly, for aged mice, there is considerable evidence that physiological changes associated with aging include impaired thermoregulation. Therefore aged mice are more sensitive to cold than young mice. However, to date, the relationships between tumor growth, chronic cold stress, thermal preference and anti-tumor immunity have not been investigated in aged mice. The major goal of this R03 application is to extend our analysis of the impact of housing temperature to aged tumor bearing mice, and determine whether aged tumor bearing mice may have an even more profound immunosuppressive response to chronic cold stress than do young mice. Here, we hypothesize that the inability of aged mice, which already face thermoregulatory challenges, to deal sufficiently with the additional cold stress imposed by housing temperatures is skewing the outcome of fundamental mouse research on aging and anti-cancer immunity. Two specific aims are proposed to address this hypothesis: Aim 1) To determine how growth rates of several different tumor models are influenced by ambient temperature in aged mice and to conduct thermal preference tests to determine whether the preferred ambient temperature of aged, tumor bearing, mice differs from that seen in young mice and Aim 2) To evaluate the balance between effector T cells and immunosuppressive cells, as well as the expression of selected cytokines/chemokines in aged naive and tumor bearing mice as a function of ambient temperature and compare to data obtained from young animals. Obtaining an accurate baseline understanding of the ability of older mice to develop anti-tumor immunity, and understanding how thermoregulatory stress may impact this ability in comparison to young mice is critical to the interpretation of experiments investigating the immune response in aged mice and ultimately for the development of clinically successful immunotherapies. This R03 application will answer, in a short time frame, the focused question of how aged tumor bearing mice are influenced by standard housing temperature, a situation which could be interfering with our full understanding of their responses to immunotherapy and other therapies.

描述（由申请人提供）：小鼠模型在衰老研究中大量使用，这些实验的结果用于预测年轻人和老年人之间免疫疗法的抗肿瘤免疫和疗效的差异。我们实验室的最新工作表明，针对小鼠研究殖民地规定的凉爽住房条件引起的热管调节挑战对我们了解幼鼠免疫反应的抗肿瘤能力的尝试，尤其是抗肿瘤效应细胞和促肿瘤效应细胞与促肌产生免疫原生物免疫抑制细胞之间的平衡。有趣的是，对于老年小鼠，有大量证据表明，与衰老相关的生理变化包括受损的体温调节。因此，老年小鼠比小鼠对寒冷更敏感。但是，迄今为止，尚未在老年小鼠中研究肿瘤生长，慢性冷应激，热偏好和抗肿瘤免疫之间的关系。该R03应用的主要目的是扩展我们对住房温度对老年肿瘤轴承小鼠的影响的分析，并确定与年轻小鼠相比，对慢性冷应激的衰老肿瘤轴承小鼠对慢性冷应激的免疫抑制反应更大。在这里，我们假设已经面临温度调节挑战的老年小鼠无法充分处理住房温度所施加的额外的冷应激，这偏向于小鼠对衰老和抗癌免疫的基本研究的结果。 Two specific aims are proposed to address this hypothesis: Aim 1) To determine how growth rates of several different tumor models are influenced by ambient temperature in aged mice and to conduct thermal preference tests to determine whether the preferred ambient temperature of aged, tumor bearing, mice differs from that seen in young mice and Aim 2) To evaluate the balance between effector T cells and immunosuppressive cells, as well as the expression of selected cytokines/chemokines in老年幼稚和肿瘤轴承小鼠与环境温度的关系，并与从幼小动物获得的数据进行比较。获得对老鼠发展抗肿瘤免疫力的能力的准确理解，并了解与年轻小鼠相比，温度调节应力如何影响这种能力，这对于研究老年小鼠的免疫反应的解释至关重要，最终对于临床成功的免疫疗法的发展最终是至关重要的。此R03应用将在短时间内回答，即对年龄肿瘤轴承小鼠的重点问题，该问题如何受标准住房温度的影响，这种情况可能会干扰我们对它们对免疫疗法和其他疗法的反应的全部理解。