Multi-modal single-cell and whole-genome sequencing of minute, frozen specimens to propel clinical applications

Y. Wang, J.L. Fan, J.C. Melms, A.D. Amin, Y. Georgis, P. Ho, S. Tagore, G. Abril-Rodríguez, J. Biermann, M. Hofree, L. Caprio, S. Berhe, S.A. Khan, B.S. Henick, A. Ribas, A.M. Taylor, G.K. Schwartz, R.D. Carvajal, E. Azizi, B. Izar

Research output: Working paper/preprintPreprint


Single-cell genomics are enabling technologies, but their broad clinical application remains challenging. We report an easily adaptable approach for single-cell transcriptome and T cell receptor (TCR)-sequencing, and matched whole-genome sequencing from tiny, frozen clinical specimens. We achieve similar quality and biological outputs while reducing artifactual signals compared to data from matched fresh tissue samples. Profiling sequentially collected melanoma samples from the KEYNOTE-001 trial, we resolve cellular, genomic, and clonotype dynamics that encapsulate molecular patterns of tumor evolution during anti-PD-1 therapy. To demonstrate applicability to banked biospecimens of rare diseases, we generate a large uveal melanoma liver metastasis single-cell and matched WGS atlas, which revealed niche-specific impairment of clonal T cell expansion. This study provides a foundational framework for propelling single-cell genomics to the clinical arena. The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
Original languageEnglish
StatePublished - 2022

Publication series

ISSN (Print)2692-8205

Bibliographical note

Export Date: 27 November 2022

Correspondence Address: Izar, B.; Department of Medicine, United States; email:

Correspondence Address: Azizi, E.; Department of Biomedical Engineering, United States; email:


  • genomics


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