SuV39H1 represses the expression of cytotoxic T-lymphocyte effector genes to promote colon tumor immune evasion

Chunwan Lu, Dafeng Yang, John D. Klement, Il Kyu Oh, Natasha Marie Savage, Jennifer L Waller, Aaron H. Colby, Mark W. Grinstaff, Nicholas H. Oberlies, Cedric J. Pearce, Zhiliang Xie, Samuel K. Kulp, Christopher C. Coss, Mitch A. Phelps, Thomas Albers, Iryna Oleksandrivna Lebedyeva, Kebin Liu

Research output: Contribution to journalArticle

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 EC 50 of 0.496 mmol/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 þ CTL-dependent manner in vivo. Our data indicate that SUV39H1 represses CTL effector gene expression and, in doing so, confers colon cancer immune escape.

Original languageEnglish (US)
Pages (from-to)414-427
Number of pages14
JournalCancer Immunology Research
Volume7
Issue number3
DOIs
StatePublished - Mar 1 2019

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Tumor Escape
Cytotoxic T-Lymphocytes
Colon
Tumor Microenvironment
Microsatellite Repeats
Genes
Neoplasms
Carcinoma
Colonic Neoplasms
Digital Libraries
Small Molecule Libraries
Enzyme Assays
Immunotherapy
T-Lymphocytes
Gene Expression
Growth

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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SuV39H1 represses the expression of cytotoxic T-lymphocyte effector genes to promote colon tumor immune evasion. / Lu, Chunwan; Yang, Dafeng; Klement, John D.; Oh, Il Kyu; Savage, Natasha Marie; Waller, Jennifer L; Colby, Aaron H.; Grinstaff, Mark W.; Oberlies, Nicholas H.; Pearce, Cedric J.; Xie, Zhiliang; Kulp, Samuel K.; Coss, Christopher C.; Phelps, Mitch A.; Albers, Thomas; Lebedyeva, Iryna Oleksandrivna; Liu, Kebin.

In: Cancer Immunology Research, Vol. 7, No. 3, 01.03.2019, p. 414-427.

Research output: Contribution to journalArticle

Lu, C, Yang, D, Klement, JD, Oh, IK, Savage, NM, Waller, JL, Colby, AH, Grinstaff, MW, Oberlies, NH, Pearce, CJ, Xie, Z, Kulp, SK, Coss, CC, Phelps, MA, Albers, T, Lebedyeva, IO & Liu, K 2019, 'SuV39H1 represses the expression of cytotoxic T-lymphocyte effector genes to promote colon tumor immune evasion', Cancer Immunology Research, vol. 7, no. 3, pp. 414-427. https://doi.org/10.1158/2326-6066.CIR-18-0126
Lu, Chunwan ; Yang, Dafeng ; Klement, John D. ; Oh, Il Kyu ; Savage, Natasha Marie ; Waller, Jennifer L ; Colby, Aaron H. ; Grinstaff, Mark W. ; Oberlies, Nicholas H. ; Pearce, Cedric J. ; Xie, Zhiliang ; Kulp, Samuel K. ; Coss, Christopher C. ; Phelps, Mitch A. ; Albers, Thomas ; Lebedyeva, Iryna Oleksandrivna ; Liu, Kebin. / SuV39H1 represses the expression of cytotoxic T-lymphocyte effector genes to promote colon tumor immune evasion. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 3. pp. 414-427.
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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 EC 50 of 0.496 mmol/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 {\th} 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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AU - Savage, Natasha Marie

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AU - Xie, Zhiliang

AU - Kulp, Samuel K.

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N2 - 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 EC 50 of 0.496 mmol/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 þ 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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