Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma.

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.

• Authors: Valsamo Anagnostou, Daniel C Bruhm, Noushin Niknafs, James R White, Xiaoshan M Shao, John William Sidhom, Julie Stein, Hua-Ling Tsai, Hao Wang, Zineb Belcaid, Joseph Murray, Archana Balan, Leonardo Ferreira, Petra Ross-Macdonald, Megan Wind-Rotolo, Alexander S Baras, Janis Taube, Rachel Karchin, Robert B Scharpf, Catherine Grasso, Antoni Ribas, Drew M Pardoll, Suzanne L Topalian, Victor E Velculescu
• Journal: Cell reports. Medicine (Cell Rep Med) Vol. 1 Issue 8 Pg. 100139 (11 17 2020) ISSN: 2666-3791 [Electronic] United States
• PMID: 33294860 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors.

Chemical References

• Immune Checkpoint Inhibitors

Topics

• B-Lymphocytes (drug effects, immunology)
• Gene Expression (drug effects, genetics, immunology)
• Gene Expression Profiling (methods)
• Genomics (methods)
• Humans
• Immune Checkpoint Inhibitors (pharmacology)
• Immunotherapy (methods)
• Melanoma (drug therapy, genetics, immunology)
• Mutation (drug effects, genetics, immunology)
• Prospective Studies
• T-Lymphocytes (drug effects, immunology)
• Transcription, Genetic (drug effects, genetics, immunology)
• Transcriptome (drug effects, genetics, immunology)