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

  • Author(s): Anagnostou, Valsamo
  • Bruhm, Daniel C
  • Niknafs, Noushin
  • White, James R
  • Shao, Xiaoshan M
  • Sidhom, John William
  • Stein, Julie
  • Tsai, Hua-Ling
  • Wang, Hao
  • Belcaid, Zineb
  • Murray, Joseph
  • Balan, Archana
  • Ferreira, Leonardo
  • Ross-Macdonald, Petra
  • Wind-Rotolo, Megan
  • Baras, Alexander S
  • Taube, Janis
  • Karchin, Rachel
  • Scharpf, Robert B
  • Grasso, Catherine
  • Ribas, Antoni
  • Pardoll, Drew M
  • Topalian, Suzanne L
  • Velculescu, Victor E
  • et al.
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.

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