Defining the role of microenvironmental ammonia in colorectal cancers

摘要： 结直肠癌是一个严重的公共卫生问题，IV期诊断的存活率只有14%， 几乎没有可行的治疗方案。结肠肿瘤由一束细胞以及它们之间的相互作用组成。 细胞对肿瘤的生长至关重要。先前的工作表明，最初的免疫-肿瘤动态是强大的抗- 但这种抗肿瘤反应随着肿瘤的进展而减弱。重新激活的免疫疗法 抗肿瘤反应目前被广泛应用于多种癌症。尽管结肠肿瘤有强大的 免疫渗透，免疫疗法基本失败，原因不明。此外，已知癌细胞可以 重新编程细胞新陈代谢以满足它们的增殖需求。癌细胞增殖产生代谢 可重新利用以维持细胞生物能量需求的废物产品。然而，很明显， 绝大多数代谢副产物在肿瘤微环境中积累。有一个关键的差距 关于代谢废物如何与免疫渗入相互作用。我的初步数据显示 KRAS突变的结肠肿瘤中积聚的氨废物增加 微环境。此外，我的初步数据显示，T细胞增殖和抗肿瘤反应是 在结肠癌中检测到的生物相关浓度显著抑制，而 其他类型的细胞基本上不受影响。我还证明了化学氨解毒可以减少肿瘤。 以依赖T细胞的方式生长。这表明，氨废物有助于减弱抗病毒作用。 结肠癌中常见的肿瘤免疫反应。我假设的数据增加了 晚期癌症患者的微环境氨是维持免疫抑制的核心 通过改变T细胞功能来维持状态。这项提案的长期目标是了解结直肠肿瘤是如何 通过代谢产物调节微环境，降低免疫效力 回应。了解这一点将推动以免疫为基础的治疗方案的发展。基于 在这些观察中，这一建议的实验重点是对肿瘤生成的调节作用 氨对T细胞功能的影响。目标1将确定KRAS突变是否在 晚期癌症。目的2将探索在肿瘤微环境中解毒氨是如何增加 T细胞免疫反应，使用遗传和化学干预。防止这种消极的异性恋- 肿瘤和T细胞之间的细胞串扰可能会改善免疫治疗方法的有效性 结直肠癌。重要的是，追求本提案中规定的目标将提供严格的科学和 在一家排名很高且得到良好支持的机构进行临床培训。这种类型的机构、设施和导师 支持将进一步推动我的职业道路，作为一名内科科学家和活跃的肿瘤学实验室。

Abstract: Colorectal cancer is a grave public health concern with only a 14% survival rate for Stage IV diagnosis, and few viable treatment options. Colon tumors are composed of a cadre of cells and the interplay between these cells is critical for tumor growth. Previous work shows that the initial immune-tumor dynamic is robustly anti- tumor, but that this anti-tumor response is attenuated as tumors progress. Immunotherapies that re-activate the anti-tumor response are currently widely used in many cancers. Although colon tumors have a robust immune infiltrate, immunotherapies have largely failed for unclear reasons. Further, cancer cells are known to reprogram cellular metabolism to meet their proliferative needs. Cancer cell proliferation produces metabolic waste products that can be re-purposed to maintain cellular bioenergetic needs. However, it is clear that the vast majority of the metabolic byproducts accumulate in the tumor microenvironment. There is a critical gap regarding how metabolic waste products interact with the immune infiltrates. My preliminary data demonstrates that KRAS mutant colon tumors have an increase in ammonia waste that accumulates in the tumor microenvironment. Moreover, my preliminary data shows that T cell proliferation and anti-tumor response is significantly inhibited at biologically relevant concentrations that have been detected in colon tumors, while other cell types are largely unaffected. I have also shown that chemical ammonia detoxification reduces tumor growth in a T cell dependent manner. This suggests that ammonia waste contributes to the attenuated anti- tumor immune response commonly observed in colon cancer. data I hypothesize that increased microenvironmental ammonia in advanced cancers is central to maintaining an immunosuppressive state by altering T cell function. The long-term goal of this proposal is to understand how colorectal tumors modulate the microenvironment through metabolic products to decrease the effectiveness of the immune response. Understanding this will advance the development of immune-based therapeutic regimens. Based on these observations, the experimental focus of this proposal is on the regulatory role of tumor-generated ammonia on T cell function. Aim 1 will determine whether KRAS mutation is driving ammonia accumulation in advanced cancers. Aim 2 will explore how detoxifying ammonia in the tumor microenvironment increases the T cell immune response, using both genetic and chemical interventions. Preventing this negative hetero- cellular cross talk between the tumor and T cells may improve the efficacy of immunotherapy approaches in colorectal cancer. Importantly, pursuing the aims specified in this proposal will provide rigorous scientific and clinical training at a highly ranked and well supported institution. This type of institutional, facility, and mentor support will further my path towards a career as a physician scientist with an active oncology laboratory.