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:10.1038/s41467-024-52079-x

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 VaknineEran 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 Ly6a^high T-cell subpopulation. Independently of the UV effect, Ly6a^high 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.

Original language	English
Article number	8354
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-52079-x
State	Published - Dec 2024

Funding

Funders	Funder number
European Research Council
Horizon 2020 Framework Programme	726225
Israel Science Foundation	2017/20

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-52079-x

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Maliah, A., Santana-Magal, N., Parikh, S., Gordon, S., Reshef, K., Sade, Y., Khateeb, A., Richter, A., Gutwillig, A., Parikh, R., Golan, T., Krissi, M., Na, M., Binshtok, G., Manich, P., Elkoshi, N., Grisaru-Tal, S., Zemser-Werner, V., Brenner, R., ... Levy, C. (2024). Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy. Nature Communications, 15(1), Article 8354. https://doi.org/10.1038/s41467-024-52079-x

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title = "Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy",

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.",

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

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doi = "10.1038/s41467-024-52079-x",

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Maliah, A, Santana-Magal, N, Parikh, S, Gordon, S, Reshef, K, Sade, Y, Khateeb, A, Richter, A, Gutwillig, A, Parikh, R, Golan, T, Krissi, M, Na, M, Binshtok, G, Manich, P, Elkoshi, N, Grisaru-Tal, S, Zemser-Werner, V, Brenner, R , Vaknine, H , Nizri, E, Moyal, L, Amitay-Laish, I, Rosemberg, L, Munitz, A , Kronfeld-Schor, N , Shifrut, E , Kobiler, O , Madi, A , Geiger, T , Carmi, Y & Levy, C 2024, 'Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy', Nature Communications, vol. 15, no. 1, 8354. https://doi.org/10.1038/s41467-024-52079-x

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AU - Maliah, Avishai

AU - Santana-Magal, Nadine

AU - Parikh, Shivang

AU - Gordon, Sagi

AU - Reshef, Keren

AU - Sade, Yuval

AU - Khateeb, Aseel

AU - Richter, Alon

AU - Gutwillig, Amit

AU - Parikh, Roma

AU - Golan, Tamar

AU - Krissi, Matan

AU - Na, Manho

AU - Binshtok, Gal

AU - Manich, Paulee

AU - Elkoshi, Nadav

AU - Grisaru-Tal, Sharon

AU - Zemser-Werner, Valentina

AU - Brenner, Ronen

AU - Vaknine, Hananya

AU - Nizri, Eran

AU - Moyal, Lilach

AU - Amitay-Laish, Iris

AU - Rosemberg, Luiza

AU - Munitz, Ariel

AU - Kronfeld-Schor, Noga

AU - Shifrut, Eric

AU - Kobiler, Oren

AU - Madi, Asaf

AU - Geiger, Tamar

AU - Carmi, Yaron

AU - Levy, Carmit

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy

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