Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma

Castle, John C.; Löewer, Martin; Boegel, Sebastian; Graaf, Jos de; Bender, Christian; Tadmor, Arbel D.; Boisguérin, Valesca; Bukur, Thomas; Sorn, Patrick; Paret, Claudia; Diken, Mustafa; Kreiter, Sebastian; Türeci, Özlem; Şahin, Uğur

doi:10.1186/1471-2164-15-190

Cited by 303 publications

(294 citation statements)

References 51 publications

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“…The most extensive study, to our knowledge, included 6 commonly-used syngeneic models with analysis limited to the expression of 27 immune-related genes and staining for 4-6 immune cell types by immunohistochemistry and flow cytometry (52). We also saw a high level of agreement in somatic mutation results with previous genetic characterization of the CT26 cell line, with >60% of mutated genes matching those in the study by Castle et al (53,54).…”

Section: Discussionsupporting

confidence: 64%

“…Disparities in somatic mutations between studies could be due to differences in cut-off levels, sensitivity and methodology, as well as cell line divergence. Our profiling of CNV, using both aCGH and WES analysis paired with the BALB/c mouse background, did not show the same large regions of triploidy and tetraploidy in CT26 seen by Castle et al (53). However, for such multichromosomal regions it is unlikely that this would be due to divergence in the CT26 cell lines, but rather due to methodological differences such as stringency of CNV calling.…”

Section: Discussionmentioning

confidence: 42%

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Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

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Sainson

et al. 2017

Cancer Immunology Research

333

381

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(word count: 239):Murine syngeneic tumor models are critical to novel immuno-based therapy development but the molecular and immunological features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly-used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We employed array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell-specific genes that suggested differences in tumor immune infiltrates between models. Further investigation using flow cytometry showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor 'inflamed' and 'non-inflamed' tumor immune infiltrate phenotypes. We also found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell-rich tumor immune infiltrate has been correlated with increased efficacy of immunotherapies in the clinic and these differences could underlie the varying response profiles to immunotherapy between the syngeneic models. This characterization highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo.4

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 42%

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Mosely

Prime

Sainson

et al. 2017

Cancer Immunology Research

333

381

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“…CT26 mouse colorectal tumor cells harbor the homozygous KRAS G12D mutation and MAPK1 and MET amplifications (16). In vitro, trametinib caused dose-dependent inhibition of cell proliferation with a mean IC 50 value of 20 nmol/L and blocked MAPK signaling measured by pERK (Fig.…”

Section: Trametinib Increases Apoptosis Markers and The Expression Ofmentioning

confidence: 93%

The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4

Liu

Mayes

Eastman

et al. 2015

Clinical Cancer Research

378

323

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Purpose: To assess the immunologic effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo.Experimental Design: Immune effects of dabrafenib and trametinib were evaluated in human CD4 þ and CD8 þ T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model.

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“…To perform infectious center assays that examined the EGFR selectivity of KGNE-BhKt-induced lateral spread, we used murine colon carcinoma CT26 cells, which have been reported to lack EGFR expression (58), and a derivative cell line that we created by transduction with human EGFR (CT26-EGFR cells). CT26 cells are susceptible to wild-type HSV and have been used by others to test the efficacy of oncolytic HSVs (59,60).…”

Section: Introduction Of Syncytial Mutations Into An Egfr-retargetedmentioning

confidence: 99%

Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus

Okubo

Uchida

Wakata

et al. 2016

J Virol

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Membrane fusion, which is the key process for both initial cell entry and subsequent lateral spread of herpes simplex virus (HSV), requires the four envelope glycoproteins gB, gD, gH, and gL. Syncytial mutations, predominantly mapped to the gB and gK genes, confer hyperfusogenicity on HSV and cause multinucleated giant cells, termed syncytia. Here we asked whether interaction of gD with a cognate entry receptor remains indispensable for initiating membrane fusion of syncytial strains. To address this question, we took advantage of mutant viruses whose viral entry into cells relies on the uniquely specific interaction of an engineered gD with epidermal growth factor receptor (EGFR). We introduced selected syncytial mutations into gB and/or gK of the EGFR-retargeted HSV and found that these mutations, especially when combined, enabled formation of extensive syncytia by human cancer cell lines that express the target receptor; these syncytia were substantially larger than the plaques formed by the parental retargeted HSV strain. We assessed the EGFR dependence of entry and spread separately by using direct entry and infectious center assays, respectively, and we found that the syncytial mutations did not override the receptor specificity of the retargeted viruses at either stage. We discuss the implications of these results for the development of more effective targeted oncolytic HSV vectors. IMPORTANCEHerpes simplex virus (HSV) is investigated not only as a human pathogen but also as a promising agent for oncolytic virotherapy. We previously showed that both the initial entry and subsequent lateral spread of HSV can be retargeted to cells expressing tumor-associated antigens by single-chain antibodies fused to a receptor-binding-deficient envelope glycoprotein D (gD). Here we introduced syncytial mutations into the gB and/or gK gene of gD-retargeted HSVs to determine whether viral tropism remained dependent on the interaction of gD with the target receptor. Entry and spread profiles of the recombinant viruses indicated that gD retargeting does not abolish the hyperfusogenic activity of syncytial mutations and that these mutations do not eliminate the dependence of HSV entry and spread on a specific gD-receptor interaction. These observations suggest that syncytial mutations may be valuable for increasing the tumor-specific spreading of retargeted oncolytic HSV vectors. Herpes simplex virus 1 (HSV-1) is an important focus of research as a common human pathogen that often causes mucocutaneous lesions. In addition, HSV has recently shown promise as a tool for the development of novel therapeutic modalities against human cancers (1).Membrane fusion is the key process required for both initial entry of the virion into cells and subsequent lateral spread of HSV-1. HSV-1 entry depends on the interaction of gD with one of its cognate receptors: herpesvirus entry mediator (HVEM), nectin-1, or 3-O-sulfated heparan sulfate (3-OS-HS) (2-4). Receptor binding triggers a conformational change in gD that in turn activates...

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Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma

Cited by 303 publications

References 51 publications

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4

Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus

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