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

Authors :
Tori N. Yamamoto
Nicholas P. Restifo
Devikala Gurusamy
Zhiya Yu
Amy K Decker
Rigel J. Kishton
Parisa Malekzadeh
Suman K. Vodnala
Drew C. Deniger
Madhusudhanan Sukumar
Douglas C. Palmer
Yogin Patel
Neville E. Sanjana
Michelle Ji
Winifred Lo
Kris C. Wood
Amanda N. Henning
Shashank J. Patel
Anna Pasetto
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

SummaryAll 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.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....22b01f07738945d244232c88d5cf0fb9
Full Text :
https://doi.org/10.1101/843185