Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model

Gorgun, Falih M.; Widen, Steven G.; Tyler, Douglas S.; Englander, Ella W.

doi:10.3389/fonc.2021.701968

Cited by 6 publications

(6 citation statements)

References 62 publications

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“…This could be explained by the high microsatellite instability status (MSI-H) of the engrafted tumor cells in the other studies. Supporting our observations, YUMM1.7 grafts have previously been shown to be insensitive to anti-PD-1 blockade (30). Although PD-1 blockade combined with BRAF and MEK inhibition has demonstrated increased overall survival in BRAF-mutant melanoma, anti-PD-1 monotherapy response greatly varies in clinic (31).…”

Section: Rac1 P29s Expression Increases Tumor Immune Cell In Ltrationsupporting

confidence: 77%

Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints

Cannon,

Budagyan,

Uribe-Alvarez

et al. 2024

Oncogene

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RAC1 P29S is the third most prevalent hotspot mutation in sun-exposed melanoma. RAC1 alterations in cancer are correlated with poor prognosis, resistance to standard chemotherapy, and insensitivity to targeted inhibitors. Although RAC1 P29S mutations in melanoma and RAC1 alterations in several other cancers are increasingly evident, the RAC1-driven biological mechanisms contributing to tumorigenesis remain unclear. Lack of rigorous signaling analysis has prevented identi cation of alternative therapeutic targets for RAC1 P29S -harboring melanomas. To investigate the RAC1 P29S -driven effect on downstream molecular signaling pathways, we generated an inducible RAC1 P29S expression melanocytic cell line and performed RNA-sequencing (RNA-seq) coupled with multiplexed kinase inhibitor beads and mass spectrometry (MIBs/MS) to establish enriched pathways from the genomic to proteomic level. Our proteogenomic analysis identi ed CDK9 as a potential new and speci c target in RAC1 P29S -mutant melanoma cells. In vitro, CDK9 inhibition impeded the proliferation of in RAC1 P29S -mutant melanoma cells and increased surface expression of PD-L1 and MHC Class I proteins. In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade signi cantly inhibited tumor growth only in melanomas that expressed the RAC1 P29S mutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy.

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Section: Rac1 P29s Expression Increases Tumor Immune Cell In Ltrationsupporting

confidence: 77%

Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints

Cannon,

Budagyan,

Uribe-Alvarez

et al. 2024

Oncogene

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“…Overall, the number of non-synonymous mutations that can lead to generation of neo-epitopes is low, making this scenario less likely. On the other hand, the MeVa2.1.dOVA model piqued our interest since we did not observe any immune-mediated growth control despite the presence of foreign antigen, which is unlike other available syngeneic melanoma models [32,35,36]. Moreover, components required for the cancer immunity cycle [54], such as strong antigen and its presentation, antigen reactive CD8 + T cells, were present in MeVa2.1.dOVA tumors.…”

Section: Discussionmentioning

confidence: 71%

“…Therefore, immunogenic variants of BRAF V600E -driven cell lines have been established by transducing them with the foreign antigen ovalbumin (OVA), by increasing the number of somatic mutations by UV irradiation, or by low dose cisplatin treatment in vitro [29,32,35,36]. Tumors arising from such immunogenic derivatives display better immune-mediated growth control compared with their parental counterparts and are responsive to ICB [29,32,35,36].…”

Section: Introductionmentioning

confidence: 99%

“…However, the repertoire of syngeneic melanoma cell lines that can be used for preclinical research to evaluate potential combination therapies involving ICB remains limited. Moreover, tumor growth of most immunogenic variants of the existing cell lines can be largely controlled by combination of anti-PD1 and anti-CTLA4, providing a narrow margin to test additional approaches [32,35,36].…”

Section: Introductionmentioning

confidence: 99%

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MeVa2.1.dOVA and MeVa2.2.dOVA: two novel BRAFV600E-driven mouse melanoma cell lines to study tumor immune resistance

et al. 2022

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While immunotherapy has become standard-of-care for cutaneous melanoma patients, primary and acquired resistance prevent long-term benefits for about half of the late-stage patients. Pre-clinical models are essential to increase our understanding of the resistance mechanisms of melanomas, aiming to improve the efficacy of immunotherapy. Here, we present two novel syngeneic transplantable murine melanoma cell lines derived from the same primary tumor induced on Braf V600E Pten −/− mice: MeVa2.1 and MeVa2.2. Derivatives of these cell lines expressing the foreign antigen ovalbumin (dOVA) showed contrasting immune-mediated tumor control. MeVa2.2.dOVA melanomas were initially controlled in immune-competent hosts until variants grew out that had lost their antigens. By contrast, MeVa2.1.dOVA tumors were not controlled despite presenting the strong OVA antigen, as well as infiltration of tumor-reactive CD8 + T cells. MeVa2.1.dOVA displayed reduced sensitivity to T cell-mediated killing and growth inhibition in vitro by both IFN-γ and TNF-α. MeVa2.1.dOVA tumors were transiently controlled in vivo by either targeted therapy, adoptive T cell transfer, regulatory T cell depletion, or immune checkpoint blockade. MeVa2.1.dOVA could thus become a valuable melanoma model to evaluate novel immunotherapy combinations aiming to overcome immune resistance mechanisms. Melanoma Res 33: 12-26

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“…Other mouse models using Yumm1.7 cells have also studied the effect of TMB on antitumor immunity and ICI therapy success. 49 , 50 These models were based on the expansion of a single cell-derived clone with increased TMB. In our model, we induced random mutations every time we treated the Yumm1.1 cells with 6TG prior to injection.…”

Section: Discussionmentioning

confidence: 99%

Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade

et al. 2022

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Immune-checkpoint inhibitors (ICI) are highly effective in reinvigorating T cells to attack cancer. Nevertheless, a large subset of patients fails to benefit from ICI, partly due to lack of the cancer neoepitopes necessary to trigger an immune response. In this study, we used the thiopurine 6-thioguanine (6TG) to induce random mutations and thus increase the level of neoepitopes presented by tumor cells. Thiopurines are prodrugs which are converted into thioguanine nucleotides that are incorporated into DNA (DNA-TG), where they can induce mutation through single nucleotide mismatching. In a pre-clinical mouse model of a mutation-low melanoma cell line, we demonstrated that 6TG induced clinical-grade DNA-TG integration resulting in an improved tumor control that was strongly T cell dependent. 6TG exposure increased the tumor mutational burden, without affecting tumor cell proliferation and cell death. Moreover, 6TG treatment re-shaped the tumor microenvironment by increasing T and NK immune cells, making the tumors more responsive to immune-checkpoint blockade. We further validated that 6TG exposure improved tumor control in additional mouse models of melanoma. These findings have paved the way for a phase I/II clinical trial that explores whether treatment with thiopurines can increase the proportion of otherwise treatment-resistant cancer patients who may benefit from ICI therapy (NCT05276284).

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Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model

Cited by 6 publications

References 62 publications

Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints

Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints

MeVa2.1.dOVA and MeVa2.2.dOVA: two novel BRAFV600E-driven mouse melanoma cell lines to study tumor immune resistance

Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade

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