Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy
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 Ly6a<sup>high</sup> T-cell subpopulation. Independently of the UV effect, Ly6a<sup>high</sup> 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.
Authors
- Noga Kronfeld‐Schor (ORCID: https://orcid.org/0000-0002-5224-3341)
- Lilach Moyal (ORCID: https://orcid.org/0000-0002-3076-1527)
- Valentina Zemser‐Werner (ORCID: https://orcid.org/0000-0003-1503-4003)
- Ronen Brenner (ORCID: https://orcid.org/0000-0002-9901-9654)
- Carmit Levy (ORCID: https://orcid.org/0000-0003-2683-8779)
- Tamar Geiger (ORCID: https://orcid.org/0000-0002-9526-197X)
- Yaron Carmi (ORCID: https://orcid.org/0000-0002-0972-0616)
- Eran Nizri (ORCID: https://orcid.org/0000-0001-7935-2372)
- Hananya Vaknine (ORCID: https://orcid.org/0000-0002-4299-9807)
- Nadine Santana-Magal (ORCID: https://orcid.org/0000-0001-9834-4634)
- Ariel Munitz (ORCID: https://orcid.org/0000-0003-1626-3019)
- Shivang Parikh (ORCID: https://orcid.org/0000-0001-6364-9307)
- Nadav Elkoshi (ORCID: https://orcid.org/0000-0003-4546-2922)
- Amit Gutwillig (ORCID: https://orcid.org/0000-0001-5288-4109)
- Sharon Grisaru‐Tal (ORCID: https://orcid.org/0000-0003-3530-308X)
- Eric Shifrut (ORCID: https://orcid.org/0000-0001-6827-0128)
- Oren Kobiler (ORCID: https://orcid.org/0000-0001-9914-3770)
- Tamar Golan (ORCID: https://orcid.org/0000-0002-1171-8224)
- Avishai Maliah (ORCID: https://orcid.org/0000-0003-3538-4633)
- Paulee Manich (ORCID: https://orcid.org/0000-0002-0484-6543)
- Asaf Madi (ORCID: https://orcid.org/0000-0003-3441-3228)
- Roma Parikh (ORCID: https://orcid.org/0000-0001-5425-4901)
- A. Richter (ORCID: https://orcid.org/0009-0004-7126-7981)
- Aseel Khateeb
- Keren Reshef
- Iris Amitay‐Laish
- Luiza Rosemberg
- Matan Krissi
- Yuval Sade
- Gal Binshtok
- Manho Na
- Sagi Gordon
Institutions
- Tel Aviv University (IL)
- Tel Aviv Sourasky Medical Center (IL)
- Rabin Medical Center (IL)
- Wolfson Medical Center (IL)
- Ragon Institute of MGH, MIT and Harvard (US)
- Academic College of Tel Aviv-Yafo (IL)
- Weizmann Institute of Science (IL)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1038/s41467-024-52079-x
- Citations
- 12
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 2.89
Funders
- European Commission