Single cell investigation of co-evolution in cancer cells and host cell immune microenvironment

Project Summary How cancer cells co-evolve with their host microenvironment immune cells remains a critical question in immunotherapy. The Wu lab focuses on the study of antigen-specific interactions and their involvement in the cellular and molecular pathways underlying anti-tumor immunity. The DFCI Translational Immunogenomics Laboratory (TIGL) was created to expand technology and computational capabilities developed within the Wu Lab and provide a dedicated resource for immunogenomic analysis across different cancer types. My current portfolio of projects is focused on developing single cell/genomics techniques to understand the crosstalk between tumor cells and immune cell populations within the tumor microenvironment and the selective pressure they exert on each other. In particular, I have implemented: (i) rhTCRseq, a sensitive and robust method to determine paired alpha and beta-TCR clonotypes in single cells as well as to perform TCR repertoire analysis in bulk RNA samples that has revealed novel insights regarding the impact of cancer vaccines on the generation of antigen-specific immunity, and is being widely applied to the monitoring of other immunotherapy trials; (ii) Slide-TCR-seq for whole transcriptome profiling and TCR clonotype identity detection in tissue sections that has been applied in different human cancer types to provide insights on the spatial relationships between clonality, neighboring cell types, and gene expression that drive T cell responses; (iii) ASAP-seq, a droplet-based 10x Genomics method for transcriptome profiling, surface protein expression detection, and ATAC- seq chromatin accessibility profiling (epigenome) in the same single cell; and (iv)nanoranger, a flexible long-read sequencing workflow and analysis pipeline to integrate single cell transcriptome profiling with genotypes. These diverse approaches have been and are being applied to several NCI-funded projects in the Wu Lab. New initiatives focus on the further development and implementation of novel single cell genomics technologies and their applications.