Gene Expression Analysis of Dog Natural Killer Cells Following Immunotherapy with Molecularly Targeted Radionuclide therapy or Inhaled IL-15

项目摘要 伴犬是一种体型较大、远缘繁殖的动物，会在现场自发地患上癌症。 一个完整的免疫系统，一个天然的原生肿瘤微环境，并在 与人类共同暴露在环境中。事实上，人类和狗共用一对 导致犬类和人类基因组之间更大相似性的进化史 和微生物群，而不是在老鼠和人之间。总而言之，这些特征使狗成为 研究癌症免疫学和癌症免疫治疗的有利翻译模型，以及 狗的临床试验允许在治疗期间研究复杂的免疫相互作用，同时还 解决癌症免疫疗法的长期疗效和毒性问题。然而，免疫 解剖需要开发可靠和有效的分析和试剂，以及更深层次的 了解狗的免疫学和免疫生物标记物是实现高影响力所必需的 翻译研究，特别是在自然杀伤(NK)细胞的背景下 物种差异是已知存在的。这项提案将建立在来自世界银行的令人兴奋的数据之上 在比较肿瘤学和小说方面拥有丰富专业知识的合作机构 免疫疗法试验正在进行中。用狗的治疗前和治疗后的PBMC样本进行试验 在接受刺激NK细胞的新的和“一流”的免疫疗法时，我们将使用RNA 测序以检查NK差异基因的表达以1)建立稳健和有效的 来自两个临床试验队列的静息和激活的犬NK细胞的基因特征；2)分析 有反应和无反应患者的NK基因签名；以及3)评估 不同NK刺激物NK基因信号的异同 预期有重叠但不同的作用机制的免疫疗法。 这项提案的结果将扩大犬类研究提供的重要联系 小鼠临床前研究和人类临床试验，并促进小说的快速翻译， 对于患有侵袭性癌症的狗和人类患者，潜在的高影响NK疗法。

Project Summary Companion dogs are large, outbred animals that develop cancer spontaneously in the presence of an intact immune system, a native autochthonous tumor microenvironment, and in the setting of shared environmental exposures with humans. In fact, humans and dogs share a paired evolutionary history which has led to greater similarities between canine and human genomes and microbiomes than between mouse and human. Together, these traits make dogs an advantageous translational model to study cancer immunology and cancer immunotherapy, and dog clinical trials allow for the study of complex immune interactions during therapy while also addressing long-term efficacy and toxicity of cancer immunotherapies. However, immune dissection requires the development of robust and validated assays and reagents, and a deeper understanding of dog immunology and immune biomarkers is necessary to achieve high impact translational studies, especially in the context of natural killer (NK) cells where significant species differences are known to exist. This proposal will build on exciting data from the collaborating institutions with significant expertise in comparative oncology and novel immunotherapy trials underway. Using pre- and on-treatment PBMC samples from dogs on trial receiving novel and “first-in-class” immunotherapies which stimulate NK cells, we will use RNA sequencing to examine NK differential gene expression to 1) establish robust and validated gene signatures of resting and activated dog NK cells from both clinical trial cohorts; 2) analyze NK gene signatures from responding and non-responding patients; and 3) evaluate for similarities and differences in NK gene signatures between respective NK stimulatory immunotherapies which are anticipated to have overlapping, but distinct, mechanisms of action. Results from this proposal will extend the important link that canine studies provide between murine pre-clinical studies and human clinical trials and facilitate the rapid translation of novel, potentially high impact NK therapies to both dog and human patients with aggressive cancers.