Antigen presentation deficiency, mesenchymal differentiation, and resistance to immunotherapy in the murine syngeneic CT2A tumor model

The GL261 and CT2A syngeneic tumor lines are frequently used as immunocompetent orthotopic mouse models of human glioblastoma (huGBM) but demonstrate distinct differences in their responses to immunotherapy. To decipher the cell-intrinsic mechanisms that drive immunotherapy resistance in CT2A-luc an...

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Published in:	Frontiers in immunology 2023-12, Vol.14, p.1297932-1297932
Main Authors:	Iorgulescu, J Bryan, Ruthen, Neil, Ahn, Ryuhjin, Panagioti, Eleni, Gokhale, Prafulla C, Neagu, Martha, Speranza, Maria C, Eschle, Benjamin K, Soroko, Kara M, Piranlioglu, Raziye, Datta, Meenal, Krishnan, Shanmugarajan, Yates, Kathleen B, Baker, Gregory J, Jain, Rakesh K, Suvà, Mario L, Neuberg, Donna, White, Forest M, Chiocca, E Antonio, Freeman, Gordon J, Sharpe, Arlene H, Wu, Catherine J, Reardon, David A
Format:	Article
Language:	eng
Subjects:	Animals Antigen Presentation antigen presentation machinery cancer Glioblastoma Humans Immunology Immunotherapy Interferon-gamma Janus Kinases Mice mouse model resistance Signal Transduction STAT Transcription Factors
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Summary:	The GL261 and CT2A syngeneic tumor lines are frequently used as immunocompetent orthotopic mouse models of human glioblastoma (huGBM) but demonstrate distinct differences in their responses to immunotherapy. To decipher the cell-intrinsic mechanisms that drive immunotherapy resistance in CT2A-luc and to define the aspects of human cancer biology that these lines can best model, we systematically compared their characteristics using whole exome and transcriptome sequencing, and protein analysis through immunohistochemistry, Western blot, flow cytometry, immunopeptidomics, and phosphopeptidomics. The transcriptional profiles of GL261-luc2 and CT2A-luc tumors resembled those of some huGBMs, despite neither line sharing the essential genetic or histologic features of huGBM. Both models exhibited striking hypermutation, with clonal hotspot mutations in RAS genes ( p.G12C in GL261-luc2 and p.Q61L in CT2A-luc). CT2A-luc distinctly displayed mesenchymal differentiation, upregulated angiogenesis, and multiple defects in antigen presentation machinery (e.g. p.Y488C and p.A275P mutations) and interferon response pathways (e.g. copy number losses of loci including IFN genes and reduced phosphorylation of JAK/STAT pathway members). The defect in MHC class I expression could be overcome in CT2A-luc by interferon-γ treatment, which may underlie the modest efficacy of some immunotherapy combinations. Additionally, CT2A-luc demonstrated substantial baseline secretion of the CCL-2, CCL-5, and CCL-22 chemokines, which play important roles as myeloid chemoattractants. Although the clinical contexts that can be modeled by GL261 and CT2A for huGBM are limited, CT2A may be an informative model of immunotherapy resistance due to its deficits in antigen presentation machinery and interferon response pathways.
ISSN:	1664-3224 1664-3224