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

描述（由申请人提供）：小鼠模型大量用于衰老研究，这些实验的结果用于预测年轻人和老年人之间的抗肿瘤免疫和免疫治疗功效的差异。我们实验室最近的工作表明，小鼠研究群体所需的凉爽住房条件所产生的温度调节挑战对我们试图了解幼龄小鼠免疫反应的抗肿瘤能力产生了未被认识的影响，特别是抗肿瘤效应细胞和促肿瘤免疫抑制细胞之间的平衡。有趣的是，对于老年小鼠，有相当多的证据表明，与衰老相关的生理变化包括体温调节受损。因此，老年小鼠比年轻小鼠对寒冷更敏感。然而，迄今为止，肿瘤生长，慢性冷应激，热偏好和抗肿瘤免疫之间的关系还没有在老年小鼠中进行研究。该R 03应用的主要目标是将我们对房屋温度对老年荷瘤小鼠的影响的分析扩展到老年荷瘤小鼠，并确定老年荷瘤小鼠是否可能比年轻小鼠对慢性冷应激具有更深刻的免疫抑制反应。在这里，我们假设已经面临体温调节挑战的老年小鼠无法充分应对房屋温度施加的额外冷应激，这扭曲了衰老和抗癌免疫力的基础小鼠研究结果。为解决这一假设，提出了两个具体目标：目的1）确定环境温度如何影响老龄小鼠中几种不同肿瘤模型的生长速率，并进行热偏好测试以确定携带肿瘤的老龄小鼠的优选环境温度是否与在年轻小鼠中观察到的不同，目的2）评估效应T细胞和免疫抑制细胞之间的平衡，以及作为环境温度的函数的在年老的未处理的和携带肿瘤的小鼠中选择的细胞因子/趋化因子的表达，并与从年轻动物获得的数据进行比较。获得对老年小鼠产生抗肿瘤免疫能力的准确基线理解，并了解与年轻小鼠相比，体温调节应激如何影响这种能力，对于解释研究老年小鼠免疫应答的实验以及最终开发临床成功的免疫疗法至关重要。该R 03应用将在短时间内回答标准饲养温度如何影响老年荷瘤小鼠的焦点问题，这种情况可能会干扰我们对免疫疗法和其他疗法的反应的全面理解。

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.