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
Affiliations
- Avishai Maliah
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- Nadine Santana-Magal
- Department of Pathology, Faculty of Medicine, Tel Aviv University
- Shivang Parikh
- The Ragon Institute of Mass General
- Sagi Gordon
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- Keren Reshef
- Department of Pathology, Faculty of Medicine, Tel Aviv University
- Yuval Sade
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- Aseel Khateeb
- Department of Pathology, Faculty of Medicine, Tel Aviv University
- Alon Richter
- Department of Pathology, Faculty of Medicine, Tel Aviv University
- Amit Gutwillig
- Department of Pathology, Faculty of Medicine, Tel Aviv University
- Roma Parikh
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- Tamar Golan
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- Matan Krissi
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- Manho Na
- Department of Pathology, Faculty of Medicine, Tel Aviv University
- Gal Binshtok
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- Paulee Manich
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- Nadav Elkoshi
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- Sharon Grisaru-Tal
- Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University
- Valentina Zemser-Werner
- Institute of Pathology, Tel Aviv Sourasky Medical Center
- Ronen Brenner
- Institute of Oncology
- Hananya Vaknine
- Institute of Pathology
- Eran Nizri
- Peritoneal Surface Malignancies and Melanoma Unit, Department of Surgery A, Tel-Aviv Sourasky Medical Center, Tel Aviv University
- Lilach Moyal
- Felsenstein Medical Research Center, Tel-Aviv University and the Division of Dermatology, Rabin Medical Center
- Iris Amitay-Laish
- Felsenstein Medical Research Center, Tel-Aviv University and the Division of Dermatology, Rabin Medical Center
- Luiza Rosemberg
- School of Zoology, Tel Aviv University
- Ariel Munitz
- Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University
- Noga Kronfeld-Schor
- School of Zoology, Tel Aviv University
- Eric Shifrut
- Department of Pathology, Faculty of Medicine, Tel Aviv University
- Oren Kobiler
- Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University
- Asaf Madi
- Department of Pathology, Faculty of Medicine, Tel Aviv University
- Tamar Geiger
- Department of Molecular Cell Biology, Weizmann Institute of Science
- Yaron Carmi
- Department of Pathology, Faculty of Medicine, Tel Aviv University
- Carmit Levy
- Department of Human Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
- DOI
- https://doi.org/10.1038/s41467-024-52079-x
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.