T-REaCT · Evolution of T cell reactivity against somatic mutations across human colon cancer stages with single-cell genomics and synthetic T cell specificity screening

Cancers are characterized by the accumulation of somatic mutations in the DNA. The human immune system can detect such mutations in cancers via T cells, which forms an important factor in the activity of clinically used cancer immunotherapies. What challenges our classic view of cancer formation are the recent breakthrough discoveries showing that somatic mutations are ubiquitously found in healthy tissues - why only some of these mutations lead to clonal outgrowths and what are the factors sustaining them? As T cells recognizing somatic mutations are abundant in cancer, it is plausible to speculate these interactions could start early in tumor evolution. Albeit of high interest, studying this phenomenon has been technically challenging as it requires the ability to obtain mutational data at single-cell resolution and interrogating T cell specificities.The T-REaCT action aims to experimentally map the co-evolution of T cells and cells carrying somatic mutations across tumor evolution. By combining two novel sets of tools and expertise from two competitive fields of synthetic T cell reactivity screening (mentor Dr Schumacher, Netherlands Cancer Institute, the Netherlands) with single-cell genomics (co-mentor Dr Landau, Weill Cornell Medicine and New York Genome Center, the US), we will create a roadmap of immune responses in human colon samples ranging from healthy tissue to adenomas to overt cancer.By describing the formation of T cell reactivity against somatic mutations from pre-malignant to the earliest steps of malignant seeding, our project has the potential to revolutionize early cancer detection and the eradication of (pre-)malignant lesions through personalized immunotherapies.