PROJECT SUMMARY The Genomics and Bioinformatics Core (Core C) will provide state-of-the-art sequencing technologies to enable immunogenomic and epigenomic measurements and corresponding bioinformatics analyses for the proposed P01 Program Projects. This Core will deploy a wide range of bulk and single cell next generation sequencing technologies optimized for the preclinical and clinical biospecimens in the Projects. Technologies supported by this Core include: whole exome sequencing for neoantigen prediction, bulk and single cell RNA-sequencing for inference of molecular and cellular networks, bulk and single cell T cell receptor sequencing to query T cell clones and their associated function, and ATAC-seq and ChIP-seq technologies to query epigenetic and tran- scriptional regulation. These technologies are complemented by optimized bioinformatics pipelines and compu- tational methods tailored to immunogenomics developed by the Core and Program Investigators. Bioinformatics methods are tailored to customized analyses of the datasets generated in Program Projects, and proteomics measurements from the Digital Pathology and Mass Cytometry Core (Core D) to support TME characterization. This Genomics and Bioinformatics Core will perform further integrative analyses of biospecimens of the thera- peutic regimens employed across Projects in this Program and promote Program Synergy. The computational methods employed in this Core will summarize the high-dimensional data to provide low dimensional summaries to the Biostatistics and Clinical Trials Core (Core B) to identify molecular and cellular determinants of immuno- therapy response and resistance to support the Projects in defining new therapeutic strategies for precision immunotherapy. The Core Co-Leaders combine expertise in genomics technologies (Dr. Yegnasubramanian) and bioinformatics (Dr. Fertig). In addition to the Program-specific goals, this Core further leverages the existing infrastructure in the NCI-designated Johns Hopkins University SKCCC Core Grant-supported Experimental and Computational Genomics Core (ECGC; Co-Director Yegnasubramanian; Co-Investigator Fertig). Both Leaders, Fertig and Yegnasubramanian, have an established track record in Genomics and Bioinformatics in collaboration with one another and Program Investigators ideally suited to enable the profiling and bioinformatics analysis proposed for the Program in this Core.