Nature Communications (Sep 2024)

Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy

  • Avishai Maliah,
  • Nadine Santana-Magal,
  • Shivang Parikh,
  • Sagi Gordon,
  • Keren Reshef,
  • Yuval Sade,
  • Aseel Khateeb,
  • Alon Richter,
  • Amit Gutwillig,
  • Roma Parikh,
  • Tamar Golan,
  • Matan Krissi,
  • Manho Na,
  • Gal Binshtok,
  • Paulee Manich,
  • Nadav Elkoshi,
  • Sharon Grisaru-Tal,
  • Valentina Zemser-Werner,
  • Ronen Brenner,
  • Hananya Vaknine,
  • Eran Nizri,
  • Lilach Moyal,
  • Iris Amitay-Laish,
  • Luiza Rosemberg,
  • Ariel Munitz,
  • Noga Kronfeld-Schor,
  • Eric Shifrut,
  • Oren Kobiler,
  • Asaf Madi,
  • Tamar Geiger,
  • Yaron Carmi,
  • Carmit Levy

DOI
https://doi.org/10.1038/s41467-024-52079-x
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 16

Abstract

Read online

Abstract T cell inhibitory mechanisms prevent autoimmune reactions, while cancer immunotherapy aims to remove these inhibitory signals. Chronic ultraviolet (UV) exposure attenuates autoimmunity through promotion of poorly understood immune-suppressive mechanisms. Here we show that mice with subcutaneous melanoma are 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 analyzes, we discover that skin-specific, UV-induced suppression of T-cells killing activity is mediated by upregulation of a Ly6ahigh T-cell subpopulation. Independently of the UV effect, Ly6ahigh T cells are induced by chronic type-1 interferon in the tumor microenvironment. Treatment with an anti-Ly6a antibody enhances the anti-tumoral cytotoxic activity of T cells and reprograms their mitochondrial metabolism via the Erk/cMyc axis. Treatment with an anti-Ly6a antibody inhibits tumor growth in mice resistant to anti-PD1 therapy. Applying our findings in humans could lead to an immunotherapy treatment for patients with resistance to existing treatments.