Single-cell transcriptomic-informed deconvolution of bulk data identifies immune checkpoint blockade resistance in urothelial cancer
Li Wang,
Sudeh Izadmehr,
John P. Sfakianos,
Michelle Tran,
Kristin G. Beaumont,
Rachel Brody,
Carlos Cordon-Cardo,
Amir Horowitz,
Robert Sebra,
William K. Oh,
Nina Bhardwaj,
Matthew D. Galsky,
Jun Zhu
Affiliations
Li Wang
Department of Precision Medicine, Aitia, Somerville, MA 02143, USA; Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA
Sudeh Izadmehr
Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA
John P. Sfakianos
Department of Urology; Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Michelle Tran
Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA; The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Kristin G. Beaumont
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Rachel Brody
Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Carlos Cordon-Cardo
Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Amir Horowitz
The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Robert Sebra
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
William K. Oh
Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA
Nina Bhardwaj
Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA; The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Matthew D. Galsky
Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA; Corresponding author
Jun Zhu
Department of Medicine, Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA; Corresponding author
Summary: Interactions within the tumor microenvironment (TME) significantly influence tumor progression and treatment responses. While single-cell RNA sequencing (scRNA-seq) and spatial genomics facilitate TME exploration, many clinical cohorts are assessed at the bulk tissue level. Integrating scRNA-seq and bulk tissue RNA-seq data through computational deconvolution is essential for obtaining clinically relevant insights. Our method, ProM, enables the examination of major and minor cell types. Through evaluation against existing methods using paired single-cell and bulk RNA sequencing of human urothelial cancer (UC) samples, ProM demonstrates superiority. Application to UC cohorts treated with immune checkpoint inhibitors reveals pre-treatment cellular features associated with poor outcomes, such as elevated SPP1 expression in macrophage/monocytes (MM). Our deconvolution method and paired single-cell and bulk tissue RNA-seq dataset contribute novel insights into TME heterogeneity and resistance to immune checkpoint blockade.
