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

项目总结

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.