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Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy

Rigel J. Kishton, Shashank J. Patel, Suman K. Vodnala, Amy E. Decker, Yogin Patel, Madhusudhanan Sukumar, Tori N. Yamamoto, Zhiya Yu, Michelle Ji, Amanda N. Henning, Devikala Gurusamy, Douglas C. Palmer, Winifred Lo, Anna Pasetto, Parisa Malekzadeh, Drew C. Deniger, Kris C. Wood, Neville E. Sanjana, Nicholas P. Restifo
doi: https://doi.org/10.1101/843185
Rigel J. Kishton
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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  • For correspondence: restifon@mail.nih.gov kishtonrj@nih.gov
Shashank J. Patel
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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Suman K. Vodnala
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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Amy E. Decker
3Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA
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Yogin Patel
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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Madhusudhanan Sukumar
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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Tori N. Yamamoto
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
4Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
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Zhiya Yu
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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Michelle Ji
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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Amanda N. Henning
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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Devikala Gurusamy
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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Douglas C. Palmer
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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Winifred Lo
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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Anna Pasetto
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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Parisa Malekzadeh
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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Drew C. Deniger
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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Kris C. Wood
3Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA
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Neville E. Sanjana
5New York Genome Center, New York, NY 10013 USA
6Department of Biology, New York University, New York, NY 10003, USA
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Nicholas P. Restifo
1Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
2Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA
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  • For correspondence: restifon@mail.nih.gov kishtonrj@nih.gov
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Summary

All current highly effective anti-tumor immunotherapeutics depend on the activity of T cells, but tumor cells can escape immune recognition by several mechanisms including loss of function in antigen presentation and inflammatory response genes, expression of immunomodulatory proteins and an immunosuppressive tumor microenvironment. In contrast, the comprehensive identification of strategies that sensitize tumor cells to immunotherapy in vivo has remained challenging. Here, we combine a two-cell type (2CT) whole-genome CRISPR-Cas9 screen with dynamic transcriptional analysis (DTA) of tumor upon T cell encounter to identify a set of genes that tumor cells express as an active defense against T cell-mediated killing. We then employed small molecule and biologic screens designed to antagonize gene products employed by tumor cells to actively defend against T cell-mediated tumor destruction and found that the inhibition of BIRC2, ITGAV or DNPEP enhanced tumor cell destruction by T cells. Mechanistically, we found that BIRC2 promoted immunotherapy resistance through inhibiting non-canonical NF-κB signaling and limiting inflammatory chemokine production. These findings show the path forward to improving T cell-mediated tumor destruction in the clinic.

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Posted November 18, 2019.
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Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy
Rigel J. Kishton, Shashank J. Patel, Suman K. Vodnala, Amy E. Decker, Yogin Patel, Madhusudhanan Sukumar, Tori N. Yamamoto, Zhiya Yu, Michelle Ji, Amanda N. Henning, Devikala Gurusamy, Douglas C. Palmer, Winifred Lo, Anna Pasetto, Parisa Malekzadeh, Drew C. Deniger, Kris C. Wood, Neville E. Sanjana, Nicholas P. Restifo
bioRxiv 843185; doi: https://doi.org/10.1101/843185
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Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy
Rigel J. Kishton, Shashank J. Patel, Suman K. Vodnala, Amy E. Decker, Yogin Patel, Madhusudhanan Sukumar, Tori N. Yamamoto, Zhiya Yu, Michelle Ji, Amanda N. Henning, Devikala Gurusamy, Douglas C. Palmer, Winifred Lo, Anna Pasetto, Parisa Malekzadeh, Drew C. Deniger, Kris C. Wood, Neville E. Sanjana, Nicholas P. Restifo
bioRxiv 843185; doi: https://doi.org/10.1101/843185

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