Using a pooled in vivo CRISPR knockout screen in syngeneic TNBC mouse models, Wang et al. identified that the E3 ubiquitin ligase Cop1 in cancer cells regulates tumor-infiltrating M2 macrophages and suppresses antitumor immunity. Multiomic analysis revealed that Cop1, via the scaffolding protein Trib2, regulates the proteasomal degradation of C/ebpδ. Loss of Cop1 stabilized C/ebpδ, allowing it to suppress expression of macrophage chemoattractant genes and leading to reduced tumor-infiltrating macrophages, suppressed tumor growth, increased survival. It also sensitized tumors to immunotherapy in breast and colorectal cancer models.
Contributed by Shishir Pant
ABSTRACT: Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpδ protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokine secretion and macrophage infiltration in the tumor microenvironment.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (2) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (4) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (8) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (10) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (14) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui 230038, China. (17) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (18) Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (19) Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (20) Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: myles_brown@dfci.harvard.edu. (22) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: xsliu@ds.dfci.harvard.edu.
