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 () and Carmit Levy ()
Additional contact information
Avishai Maliah: Tel Aviv University
Nadine Santana-Magal: Tel Aviv University
Shivang Parikh: The Ragon Institute of Mass General
Sagi Gordon: Tel Aviv University
Keren Reshef: Tel Aviv University
Yuval Sade: Tel Aviv University
Aseel Khateeb: Tel Aviv University
Alon Richter: Tel Aviv University
Amit Gutwillig: Tel Aviv University
Roma Parikh: Tel Aviv University
Tamar Golan: Tel Aviv University
Matan Krissi: Tel Aviv University
Manho Na: Tel Aviv University
Gal Binshtok: Tel Aviv University
Paulee Manich: Tel Aviv University
Nadav Elkoshi: Tel Aviv University
Sharon Grisaru-Tal: Tel Aviv University
Valentina Zemser-Werner: Tel Aviv Sourasky Medical Center
Ronen Brenner: Institute of Oncology
Hananya Vaknine: Institute of Pathology
Eran Nizri: Tel Aviv University
Lilach Moyal: Tel-Aviv University and the Division of Dermatology, Rabin Medical Center
Iris Amitay-Laish: Tel-Aviv University and the Division of Dermatology, Rabin Medical Center
Luiza Rosemberg: Tel Aviv University
Ariel Munitz: Tel Aviv University
Noga Kronfeld-Schor: Tel Aviv University
Eric Shifrut: Tel Aviv University
Oren Kobiler: Tel Aviv University
Asaf Madi: Tel Aviv University
Tamar Geiger: Weizmann Institute of Science
Yaron Carmi: Tel Aviv University
Carmit Levy: Tel Aviv University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52079-x

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