Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2024

Crosslinking of Ly6a metabolically reprogram CD8 T cells for cancer immunotherapy (#111)

Avishy maliach 1 , Yaron Carmi 2 , carmit levy 1
  1. Department of Human Genetics and Biochemistry, , Tel Aviv University, Tel Aviv, Israel
  2. Department of Pathology, Tel Aviv University, Tel Aviv, Israel

T-cell inhibitory mechanisms prevent autoimmune reactions. While cancer immunotherapy aims to remove these inhibitory signals, chronic UVB exposure attenuates autoimmunity through promotion of unknown immune suppression mechanisms. We here show that mice with subcutaneous melanomas were unresponsive to checkpoint blockade therapy following chronic UV irradiation. This no responsiveness was due to the suppression of skin-draining lymph node T-cells' killing ability. Using mass cytometry analysis and single cell RNA sequencing, we uncovered a skin-specific UV-induced suppression of T-cells marked by upregulation of Ly6a. Ly6ahigh T-cells are subtype of exhausted T cells that induced by the chronic inhibitory effect of type-1 interferon following UV exposure. Out of the UV context, we found enrichment of exposed Ly6ahigh T-cells in the tumor microenvironment and demonstrate that Ly6a crosslinking enhances T-cell anti-tumoral cytotoxic activity, change T cells proteomic profile and reprograms their mitochondrial metabolism. Remarkably, in vivo treatment with anti-Ly6a antibody significantly inhibited tumor growth in mice resistant to anti-PD1 therapy. Appling our findings in humans could lead to a new immunotherapy treatment for patients with resistance to existing treatments.