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Gene expression profiles of melanoma tumor samples from patients treated with checkpoint inhibitors (mouse)

ABSTRACT: Checkpoint inhibitors have improved outcomes for patients with metastatic melanoma, but primary or acquired resistance often occurs. We used the mouse melanoma cell line B16, originally derived from C57BL6 mice, to model changes in tumor cell gene expression that occur with acquired resistance to checkpoint inhibitors. B16 cells used were engineered to express the fluorescent marker tdTomato, to assist monitoring and cell sorting. Previously-untreated B16 cells (F0) were inoculated into C57BL6 mice, followed by treatment with triple-checkpoint inhibitor therapy (3I) with combined antibodies to CTLA4, PD-1, and PD-L1. Tumors that emerged despite immune selection pressure were harvested, grown again in vitro as a cell line, and then re-inoculated into a new generation of mice. This was repeated for 4 generations (F4) until inoculations were 100% successful at generating immune-resistant tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE122221 | GEO | 2020/11/01

REPOSITORIES: GEO

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Project description:Dietary tyrosine regulating melanoma progression has been well-recognized. However, whether tyrosine-based melanin anabolism contributes to pulmonary and cerebral organotropic colonization of melanoma remains elusive. Furthermore, how to inhibit multi-organ metastasis by interfering tyrosinase activity of melanoma cells and function of immunocytes needs to be designed and validated. Patients derived melanoma cells and mouse B16 melanoma cells with different pigment were employed in this investigation. Tyrosine content dynamics in tumors and multiple organs during the melanoma progression were monitored, and tyrosine-based melanin synthesis ability of melanoma cells derived from multi-organ were detected. Additionally, we also adopted the RNA-seq, flowcytometry, real-time PCR and composite metastasis mouse model to analyze organotropic colonization and to design therapeutic strategies. B16 melanoma cells with high activity of tyrosinase and sensitivity of tyrosine utilization for melanin synthesis (Tyr-H cells) easily colonized in the lung, while B16 melanoma cells without above characteristics (Tyr-L cells) exhibited potent proliferation in the brain. Mechanistically, Tyr-H cells recruited and trained neutrophils and macrophages to build up the pulmonary metastatic niche dependent on highly secreted CXCL1 and CXCL2 and an excess melanosome accumulation-induced cell death. Tyr-L cells enhanced PD-L1 expression in tumor-infiltrated macrophages when they are progressing in the brain. Accordingly, intervention of tyrosinase activity (2-Ethoxybenzamide or hydroquinone), together with inhibitors to phagocytosis (GSK343) or chemotaxis (SB225002) suppress organotropic colonization and significantly improve the survival of immune checkpoint blockade (PD1 antibody) treated melanoma bearing mice. The heterogeneity of melanoma cells in utilization of tyrosine is associated with organotropic colonization, providing the basis for developing strategies to combat melanoma and prevent their metastasis.

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Gene expression profiles of melanoma tumor samples from patients treated with checkpoint inhibitors (mouse)

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