Convergent Identification and Interrogation of Tumor-Intrinsic Factors that Modulate Cancer Immunity In Vivo

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Abstract

The genetic makeup of cancer cells directs oncogenesis and influences the tumor microenvironment. In this study, we massively profiled genes that functionally drive tumorigenesis using genome-scale in vivo CRISPR screens in hosts with different levels of immunocompetence. As a convergent hit from these screens, Prkar1a mutant cells are able to robustly outgrow as tumors in fully immunocompetent hosts. Functional interrogation showed that Prkar1a loss greatly altered the transcriptome and proteome involved in inflammatory and immune responses as well as extracellular protein production. Single-cell transcriptomic profiling and flow cytometry analysis mapped the tumor microenvironment of Prkar1a mutant tumors and revealed the transcriptomic alterations in host myeloid cells. Taken together, our data suggest that tumor-intrinsic mutations in Prkar1a lead to drastic alterations in the genetic program of cancer cells, thereby remodeling the tumor microenvironment. Codina et al. performed genome-scale in vivo CRISPR screens that robustly identified multiple regulators of tumor-intrinsic factors that alter the ability of cells to grow as tumors across different levels of immunocompetence. Characterization of Prkar1a, a convergent hit from these screens, showed that its knockdown leads to drastic alterations in the phosphoproteome and transcriptome, corresponding to changes in the tumor microenvironment.

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Codina, A., Renauer, P. A., Wang, G., Chow, R. D., Park, J. J., Ye, H., … Chen, S. (2019). Convergent Identification and Interrogation of Tumor-Intrinsic Factors that Modulate Cancer Immunity In Vivo. Cell Systems, 8(2), 136-151.e7. https://doi.org/10.1016/j.cels.2019.01.004

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