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

Adan Codina; Paul A Renauer; Guangchuan Wang; Ryan D Chow; Jonathan J Park; Hanghui Ye; Kerou Zhang; Matthew B Dong; Brandon Gassaway; Lupeng Ye; Youssef Errami; Li Shen; Alan Chang; Dhanpat Jain; Roy S Herbst; Marcus Bosenberg; Jesse Rinehart; Rong Fan; Sidi Chen

doi:10.1016/j.cels.2019.01.004

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

Cell Syst. 2019 Feb 27;8(2):136-151.e7. doi: 10.1016/j.cels.2019.01.004. Epub 2019 Feb 20.

Authors

Adan Codina¹, Paul A Renauer¹, Guangchuan Wang², Ryan D Chow³, Jonathan J Park³, Hanghui Ye², Kerou Zhang⁴, Matthew B Dong³, Brandon Gassaway⁵, Lupeng Ye², Youssef Errami², Li Shen², Alan Chang², Dhanpat Jain⁶, Roy S Herbst⁷, Marcus Bosenberg⁸, Jesse Rinehart⁵, Rong Fan⁴, Sidi Chen⁹

Affiliations

¹ System Biology Institute, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; MCGD Program, Yale University, 333 Cedar Street, New Haven, CT 06510, USA.
² System Biology Institute, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA.
³ System Biology Institute, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Yale M.D.-Ph.D. Program, 367 Cedar Street, New Haven, CT 06510, USA.
⁴ Center for Cancer Systems Biology, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Department of Biomedical Engineering, Yale University, 55 Prospect Street, New Haven, CT 06511, USA.
⁵ System Biology Institute, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Department of Cellular and Molecular Physiology, Yale University, 333 Cedar St., New Haven, CT 06520, USA.
⁶ Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
⁷ Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA; Smilow Cancer Hospital, 35 Park St, New Haven, CT 06510, USA; Yale Comprehensive Cancer Center, 20 York Street, Ste North Pavilion 4, New Haven, CT 06510, USA.
⁸ Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Comprehensive Cancer Center, 20 York Street, Ste North Pavilion 4, New Haven, CT 06510, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA.
⁹ System Biology Institute, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; MCGD Program, Yale University, 333 Cedar Street, New Haven, CT 06510, USA; Yale M.D.-Ph.D. Program, 367 Cedar Street, New Haven, CT 06510, USA; Yale Comprehensive Cancer Center, 20 York Street, Ste North Pavilion 4, New Haven, CT 06510, USA; Immunobiology Program, The Anlyan Center, 300 Cedar Street, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: sidi.chen@yale.edu.

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.

Keywords: Prkar1a; cancer genomics; cancer immunology; in vivo CRISPR screen; transformation.

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

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