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Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

View ORCID ProfileAjaykumar Vishwakarma, Nicholas Bocherding, Michael S. Chimenti, Purshottam Vishwakarma, Kenneth Nepple, Aliasger Salem, Russell W. Jenkins, Weizhou Zhang, Yousef Zakharia
doi: https://doi.org/10.1101/824482
Ajaykumar Vishwakarma
1Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
2Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
3Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
4Cancer Biology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City IA, USA
5Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
6Department of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
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  • ORCID record for Ajaykumar Vishwakarma
Nicholas Bocherding
4Cancer Biology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City IA, USA
5Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
7Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
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Michael S. Chimenti
8Iowa Institute of Human Genetics, Bioinformatics Division, University of Iowa, Iowa City, IA, USA
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Purshottam Vishwakarma
9The MathWorks, Inc., Natick, MA, USA
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Kenneth Nepple
10Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
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Aliasger Salem
5Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
6Department of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
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Russell W. Jenkins
1Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
2Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
3Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
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  • For correspondence: rwjenkins@partners.org zhangw@ufl.edu yousef-zakharia@uiowa.edu
Weizhou Zhang
11Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA
12University of Florida Health Cancer Center, University of Florida, Gainesville, FL, USA
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  • For correspondence: rwjenkins@partners.org zhangw@ufl.edu yousef-zakharia@uiowa.edu
Yousef Zakharia
5Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
10Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
13Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
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  • For correspondence: rwjenkins@partners.org zhangw@ufl.edu yousef-zakharia@uiowa.edu
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Abstract

The immune cells within the tumor microenvironment are considered key determinants of response to cancer immunotherapy. Immune checkpoint blockade (ICB) has transformed the treatment of clear cell renal cell carcinoma (ccRCC), although the role of specific immune cell states remains unclear. To characterize the tumor microenvironment (TME) of ccRCC, we applied single-cell RNA sequencing (scRNA-seq) along with paired T cell receptor sequencing to map the transcriptomic heterogeneity of 24,904 individual CD45+ lymphoid and myeloid cells in matched tumor and blood from patients with ccRCC. We identified multiple distinct immune cell phenotypes for B and T (CD4 and CD8) lymphocytes, natural kill (NK) cells, and myeloid cells. Evaluation of T cell receptor (TCR) sequences revealed limited shared clonotypes between patients, whereas tumor-infiltrating T cell clonotypes were frequently found in peripheral blood, albeit in lower abundance. We further show that the circulating CD4+ T cell clonality is far less diverse than peripheral CD8+. Evaluation of myeloid subsets revealed unique gene programs defining monocytes, dendritic cells and tumor-associated macrophages. In summary, here we have leveraged scRNA-seq to refine our understanding of the relative abundance, diversity and complexity of the immune landscape of ccRCC. This report represents the first characterization of ccRCC immune landscape using scRNA-seq. With further characterization and functional validation, these findings may identify novel sub-populations of immune cells amenable to therapeutic intervention.

One Sentence Summary Single-cell RNA-sequencing reveals unique lymphoid and myeloid gene programs with putative functions in clear cell renal cancer patients

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Posted October 31, 2019.
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Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq
Ajaykumar Vishwakarma, Nicholas Bocherding, Michael S. Chimenti, Purshottam Vishwakarma, Kenneth Nepple, Aliasger Salem, Russell W. Jenkins, Weizhou Zhang, Yousef Zakharia
bioRxiv 824482; doi: https://doi.org/10.1101/824482
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Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq
Ajaykumar Vishwakarma, Nicholas Bocherding, Michael S. Chimenti, Purshottam Vishwakarma, Kenneth Nepple, Aliasger Salem, Russell W. Jenkins, Weizhou Zhang, Yousef Zakharia
bioRxiv 824482; doi: https://doi.org/10.1101/824482

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