PROJECT SUMMARY The adaptive immune system is responsible for the specific recognition and elimination of antigens originating from infection and disease. It recognizes antigens via an immense array of antigen-binding antibodies (B-cell receptors, BCRs) and T-cell receptors (TCRs), the immune repertoire. Because of the enormous breadth of epitopes recognized by immune repertoires, immune repertoires are extremely diverse and dynamic. Advances in immune receptor sequencing (Rep-seq), such as next generation sequencing, have driven the quantitative and molecular-level profiling of immune repertoires, thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. However, current analysis tools lack the ability to track and examine the dynamic nature of the repertoire across serial time points or to identify the common features across repertoires thoroughly and efficiently. We will develop computationally efficient methods with advanced machine learning techniques, including network analysis, feature selection and classification, and advanced statistical approaches, to interrogate and measure immune repertoire architecture longitudinally, to identify common features across repertoires and to assess their clinical relevance. Network analysis is a powerful approach that can identify TCRs sharing antigen specificity and highly mutable BCR, which can help to develop or improve existing immunotherapeutics and immunodiagnostics. However, network construction is computationally expensive, therefore, we will develop an adaptive subsampling strategy to relieve computation burden. We will implement the proposed methods on two studies to better illustrate the diversity and richness of the data to demonstrate the flexibility and power of the proposed tools. Furthermore, we will develop bioinformatics software by incorporating the proposed methods and techniques to tackle the complexity of the Rep-seq data in a translational fashion and provide a comprehensive platform with user-friendly visualization tools.

PROJECT NARRATIVE T cells and B cells as the crucial components of the adaptive immune system. Next generation sequencing of the T and B cell receptors can be used to profile the T and B cell repertoire (Rep-seq). We hypothesize that understanding the network architecture of immune repertoire will reveal the role of adaptive immune response to cancer immunotherapy. We propose to apply network analysis with advanced statistical approaches and computational techniques on Rep-seq data to unravel how the adaptive immune system is altered by immunotherapy within clinical responders and non-responders.