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Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.

ABSTRACT: T cell inhibitory mechanisms prevent autoimmune reactions, while cancer immunotherapy aims to remove these inhibitory signals, Chronic UV exposure attenuates autoimmunity through promotion of unknown immune-suppressive mechanisms. Here we showed that mice with subcutaneous melanoma were not responsive to anti-PD1 immunotherapy following chronic UV irradiation, given prior to tumor injection, due to the suppression of T cell killing ability in skin-draining lymph nodes. Using mass cytometry and single-cell RNA-sequencing analyses, we discovered that skin-specific, UV-induced suppression of T-cells killing activity is mediated by upregulation of Ly6ahigh T-cells subpopulation. Independently of the UVB effect, Ly6ahigh T cells were induced by chronic type-1 interferon in the tumor microenvironment. Treatment with an anti-Ly6a antibody enhanced the anti-tumoral cytotoxic activity of T cells and reprogrammed their mitochondrial metabolism via the Erk/cMyc axis. Remarkably, treatment with anti-Ly6a antibody significantly inhibited tumor growth in mice resistant to anti-PD1 therapy. Applying our findings in humans could lead to a new immunotherapy treatment for patients with resistance to existing treatments.

ORGANISM(S): Mus musculus

PROVIDER: GSE272861 | GEO | 2024/08/04

REPOSITORIES: GEO

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Crosslinking of Ly6a metabolically reprogram CD8 T cells for cancer immunotherapy.

Project description:To evaluate the downstream effects of anti-Ly6a crosslinking, we examined the effect of anti-Ly6a antibodies on CD8+ T cell activity in the presence and absence of target tumor cells by high-resolution mass spectrometry proteomic analyses. Spleen cells were isolated from gp10025–33 TCR transgenic mice and incubated for 3 days with IL-2, IFNα, and gp10025–33 peptide. Next, CD8+ T-cells were isolated and incubated overnight with anti-Ly6a antibody (or IgG with or without B16F10 melanoma cells. CD8+ T-cells were then sorted and subjected to proteomic analysis using high-resolution mass spectrometry

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Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.

Project description:Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.

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Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [Bulk-seq]

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