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Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy
- 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.
- Subjects :
- 0303 health sciences
Chemokine
Tumor microenvironment
biology
medicine.medical_treatment
T cell
Antigen presentation
Druggability
Immunotherapy
3. Good health
03 medical and health sciences
0302 clinical medicine
medicine.anatomical_structure
Cancer immunotherapy
030220 oncology & carcinogenesis
medicine
biology.protein
Cancer research
ITGAV
030304 developmental biology
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....22b01f07738945d244232c88d5cf0fb9
- Full Text :
- https://doi.org/10.1101/843185