ABSTRACT Despite the recognition of the contribution of the immune system to cancer response to ionizing radiation, successful translation to the clinic is lagging. We are proposing to adapt the ROBIN mechanisms of research to enable a deep dive into the field of radiation (RT) and immunity. Representatives from seven international academic centers already engaged in RT and immunity research have converged to participate in a small prospective clinical trial (accrual: 25 patients in US and 25 patients in Europe), to synergize and accelerate discovery. The setting of preoperative short course radiotherapy (SCRT) in rectal cancer, has emerged as ideal for the scientific questions posed. SCRT is a standard treatment, preceded and followed by colonoscopies to respectively assess tumor baseline extent and response (at the end of RT): during each colonoscopy consenting patients can donate a tumor biopsy, as well as stool and blood (PBMC) samples. The same set of specimens can be harvested, six weeks later at surgery, where research sampling of lymph nodes will also be possible, within and outside the RT field. These sequential sets of tissues will enable us to conduct cutting edge multiple “omics” approaches to study irradiated normal and cancer tissue and the microbiome in the RT field. The PBMC analysis will allow correlation at a single cell level between RT-induced oxidative stress, changes in immunophenotype and PBMC biology. Similarly, the ability to analyze lymph nodes harvested inside and outside the radiation field will allow to pinpoint at the single cell level the RT effects on each immune subpopulation. The longitudinal analysis on cancer biopsy, collected before and after RT and at surgery, will give a snapshot on the RT-induced “omics” changes. An orthogonal radiomic study will analyze MR images obtained before SCRT and before surgery (also standard imaging procedures in rectal cancer) together with images obtained at CT simulation. Compliance with international regulations for data sharing, standardization of procedures and data acquisition and harmonization of uploaded data will be essential to this effort. Advanced bioinformatics tools will be applied through a dedicated Data Sharing and Integrative Analysis Core, capable to deconvolute and interpret complex biological and imaging data, sorted by utilizing NCI FireCloud workspaces. By converging experienced clinical investigators, bio-scientists and bio-informaticians to address fundamental radiation biology questions, this ROBIN will rapidly enable unprecedented discovery that will be shared with the ROBIN network and the scientific community at large. Finally, since inception, ROBIN has revealed an optimal environment for cross-training and cross-fertilization of the scientists and clinicians involved in the grant preparation and has created a robust foundation for the proposed Cross Training Core, a novel structure to form future leaders in radiation oncology and biology, a task eac...