Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma
Valsamo Anagnostou, Daniel C. Bruhm, Noushin Niknafs, James R. White, Xiaoshan M. Shao, John-William Sidhom, Julie E. Stein, Hua-Ling Tsai, Hao Wang, Zineb Belcaid, Joseph C. Murray, Archana Balan, Leonardo Ferreira, Petra Ross‐Macdonald, Megan Wind‐Rotolo, Alexander S. Baras, Janis M. Taube, Rachel Karchin, Robert B. Scharpf, Catherine S. Grasso, Antoni Ribas, Drew M. Pardoll, Suzanne L. Topalian, Victor E. Velculescu
Abstract
In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.