2. Academic Validation
  3. SUV39H1 Represses the Expression of Cytotoxic T-Lymphocyte Effector Genes to Promote Colon Tumor Immune Evasion

SUV39H1 Represses the Expression of Cytotoxic T-Lymphocyte Effector Genes to Promote Colon Tumor Immune Evasion

  • Cancer Immunol Res. 2019 Mar;7(3):414-427. doi: 10.1158/2326-6066.CIR-18-0126.
Chunwan Lu 1 2 3,  Dafeng Yang 4 2 3,  John D Klement 4 2 3,  Il Kyu Oh 4,  Natasha M Savage 5,  Jennifer L Waller 6,  Aaron H Colby 7 8,  Mark W Grinstaff 7 8,  Nicholas H Oberlies 9,  Cedric J Pearce 10,  Zhiliang Xie 11,  Samuel K Kulp 11,  Christopher C Coss 11,  Mitch A Phelps 11,  Thomas Albers 12,  Iryna O Lebedyeva 12,  Kebin Liu 1 2 3
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia. Clu@augusta.edu Kliu@augusta.edu.
  • 2 Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia.
  • 3 Charlie Norwood VA Medical Center, Augusta, Georgia.
  • 4 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.
  • 5 Department of Pathology, Medical College of Georgia, Augusta, Georgia.
  • 6 Department of Population Health Sciences, Medical College of Georgia, Augusta, Georgia.
  • 7 Ionic Pharmaceuticals, Brookline, Massachusetts.
  • 8 Department of Biomedical Engineering, Boston University, Boston, Massachusetts.
  • 9 Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina.
  • 10 Mycosynthetix, Inc., Hillsborough, North Carolina.
  • 11 Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio.
  • 12 Department of Chemistry and Physics, Augusta University, Augusta, Georgia.
PMID: 30610059 DOI: 10.1158/2326-6066.CIR-18-0126
Abstract

Despite the presence of CTLs in the tumor microenvironment, the majority of immunogenic human colon Cancer does not respond to Immune Checkpoint Inhibitor immunotherapy, and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unknown. We report here that CTLs were present in both MSI and microsatellite stable colon tumors. The expression of the H3K9me3-specific Histone Methyltransferase SUV39H1 was significantly elevated in human colon carcinoma compared with normal colon tissues. Using a mouse colon carcinoma model, we further determined that tumor-infiltrating CTLs in the colon tumor microenvironment have high expression of SUV39H1. To target SUV39H1 in the tumor microenvironment, a virtual chemical library was screened on the basis of the SET (suppressor of variegation 3-9, enhancer of zeste and trithorax) domain structure of the human SUV39H1 protein. Functional enzymatic activity assays identified a small molecule that inhibits SUV39H1 enzymatic activity. On the basis of the structure of this small molecule, we modified it and chemically synthesized a small molecule, termed F5446, which has an EC50 of 0.496 μmol/L for SUV39H1 enzymatic activity. H3K9me3 was enriched in the promoters of GZMB, PRF1, FASLG, and IFNG in quiescent T cells. F5446 inhibited H3K9me3, thereby upregulating expression of these effectors in tumor-infiltrating CTLs and suppressing colon carcinoma growth in a CD8+ CTL-dependent manner in vivo Our data indicate that SUV39H1 represses CTL effector gene expression and, in doing so, confers colon Cancer immune escape.

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