Technical choices significantly alter the adaptive immune response against immunocompetent murine gliomas in a model-dependent manner

Noffsinger, Breanna; Witter, Alexandra R.; Sheybani, Natasha D.; Xiao, Aizhen; Manigat, Laryssa; Zhong, Qing; Taori, Suchet; Harris, Tajie H.; Bullock, Tim N; Price, Richard J.; Purow, Benjamin

doi:10.1007/s11060-021-03822-7

Cited by 8 publications

(4 citation statements)

References 43 publications

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“…Along with NK cells, they promote tumor regression via the release of the cytolytic content of their granules such as perforin, granzymes, and the cytokine IFN-γ 33 . Our data correlates with similar observations in other tumor mouse models, such as for glioblastoma, where the injection of CT2A-Luc cells in the brain drastically increased the number of T cells locally, compared with wild-type controls 34 , and murine lung carcinoma, as seen by increased tumor-infiltrating lymphocytes (TILs) and decreased tumor-induced myeloid-derived suppressor cells (MDSCs) in Luc-expressing tumors, in comparison to non-Luc tumors 18 .…”

Section: Discussionsupporting

confidence: 90%

KPC-luciferase-expressing cells elicit an anti-tumor immune response in a mouse model of pancreatic cancer

Ferrari,

Ramos-Gomes,

Alves

et al. 2024

Sci Rep

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Mouse models for the study of pancreatic ductal adenocarcinoma (PDAC) are well-established and representative of many key features observed in human PDAC. To monitor tumor growth, cancer cells that are implanted in mice are often transfected with reporter genes, such as firefly luciferase (Luc), enabling in vivo optical imaging over time. Since Luc can induce an immune response, we aimed to evaluate whether the expression of Luc could affect the growth of KPC tumors in mice by inducing immunogenicity. Although both cell lines, KPC and Luc transduced KPC (KPC-Luc), had the same proliferation rate, KPC-Luc tumors had significantly smaller sizes or were absent 13 days after orthotopic cell implantation, compared to KPC tumors. This coincided with the loss of bioluminescence signal over the tumor region. Immunophenotyping of blood and spleen from KPC-Luc tumor-bearing mice showed a decreased number of macrophages and CD4+ T cells, and an increased accumulation of natural killer (NK) cells in comparison to KPC tumor mice. Higher infiltration of CD8+ T cells was found in KPC-Luc tumors than in their controls. Moreover, the immune response against Luc peptide was stronger in splenocytes from mice implanted with KPC-Luc cells compared to those isolated from KPC wild-type mice, indicating increased immunogenicity elicited by the presence of Luc in the PDAC tumor cells. These results must be considered when evaluating the efficacy of anti-cancer therapies including immunotherapies in immunocompetent PDAC or other cancer mouse models that use Luc as a reporter for bioluminescence imaging.

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Section: Discussionsupporting

confidence: 90%

KPC-luciferase-expressing cells elicit an anti-tumor immune response in a mouse model of pancreatic cancer

Ferrari,

Ramos-Gomes,

Alves

et al. 2024

Sci Rep

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“…Whereas GL261 is sensitive to various immunotherapeutic modalities, CT2A is broadly resistant to single-agent immunotherapies aimed at T cell responses – including immune checkpoint inhibitors, vaccine therapy, and oncolytic virotherapy – which can be explained by our findings of deficits in antigen presentation machinery and interferon response in CT2A-luc ( 12 , 17 – 21 ). The immunotherapeutic resistance of CT2A persists even with the ectopic expression of luciferase, which has been shown to confer increased immunogenicity to cell lines ( 51 ). Accordingly, ectopic expression of luciferase is a notable limitation of these models.…”

Section: Discussionmentioning

confidence: 99%

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

Iorgulescu,

Ruthen,

Ahn

et al. 2023

Front. Immunol.

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BackgroundThe 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.MethodsTo 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.ResultsThe 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 (Kras p.G12C in GL261-luc2 and Nras p.Q61L in CT2A-luc). CT2A-luc distinctly displayed mesenchymal differentiation, upregulated angiogenesis, and multiple defects in antigen presentation machinery (e.g. Tap1 p.Y488C and Psmb8 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.ConclusionAlthough 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.

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“…Similarly, CT-2A-Luc glioma-bearing mice were found to have a higher number of infiltrating T cells in the brain compared with CT-2A controls. Additionally, CT-2A-Luc mice treated with anti-PD1 survived much longer than untreated CT-2A-Luc mice, whereas CT-2A mice treated with anti-PD1 experienced no survival benefit [ 47 ]. This finding should encourage caution when interpreting the positive results of preclinical immunotherapy studies that employ luciferase-expressing cell lines.…”

Section: Syngeneic Murine Glioma Cell Linesmentioning

confidence: 99%

Translational Models in Glioma Immunotherapy Research

Ren

Lee

et al. 2023

Current Oncology

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Immunotherapy is a promising therapeutic domain for the treatment of gliomas. However, clinical trials of various immunotherapeutic modalities have not yielded significant improvements in patient survival. Preclinical models for glioma research should faithfully represent clinically observed features regarding glioma behavior, mutational load, tumor interactions with stromal cells, and immunosuppressive mechanisms. In this review, we dive into the common preclinical models used in glioma immunology, discuss their advantages and disadvantages, and highlight examples of their utilization in translational research.

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Technical choices significantly alter the adaptive immune response against immunocompetent murine gliomas in a model-dependent manner

Cited by 8 publications

References 43 publications

KPC-luciferase-expressing cells elicit an anti-tumor immune response in a mouse model of pancreatic cancer

KPC-luciferase-expressing cells elicit an anti-tumor immune response in a mouse model of pancreatic cancer

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

Translational Models in Glioma Immunotherapy Research

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