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IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction

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IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction. / Shiri, Ahmad Mustafa; Zhang, Tao; Bedke, Tanja; Zazara, Dimitra E; Zhao, Lilan; Lücke, Jöran; Sabihi, Morsal; Fazio, Antonella; Zhang, Siwen; Tauriello, Daniele V F; Batlle, Eduard; Steglich, Babett; Kempski, Jan; Agalioti, Theodora; Nawrocki, Mikołaj; Xu, Yang; Riecken, Kristoffer; Liebold, Imke; Brockmann, Leonie; Konczalla, Leonie; Bosurgi, Lidia; Mercanoglu, Baris; Seeger, Philipp; Küsters, Natalie; Lykoudis, Panagis M; Heumann, Asmus; Arck, Petra C; Fehse, Boris; Busch, Philipp; Grotelüschen, Rainer; Mann, Oliver; Izbicki, Jakob R; Hackert, Thilo; Flavell, Richard A; Gagliani, Nicola; Giannou, Anastasios D; Huber, Samuel.

in: J HEPATOL, Jahrgang 80, Nr. 4, 04.2024, S. 634-644.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Shiri, AM, Zhang, T, Bedke, T, Zazara, DE, Zhao, L, Lücke, J, Sabihi, M, Fazio, A, Zhang, S, Tauriello, DVF, Batlle, E, Steglich, B, Kempski, J, Agalioti, T, Nawrocki, M, Xu, Y, Riecken, K, Liebold, I, Brockmann, L, Konczalla, L, Bosurgi, L, Mercanoglu, B, Seeger, P, Küsters, N, Lykoudis, PM, Heumann, A, Arck, PC, Fehse, B, Busch, P, Grotelüschen, R, Mann, O, Izbicki, JR, Hackert, T, Flavell, RA, Gagliani, N, Giannou, AD & Huber, S 2024, 'IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction', J HEPATOL, Jg. 80, Nr. 4, S. 634-644. https://doi.org/10.1016/j.jhep.2023.12.015

APA

Shiri, A. M., Zhang, T., Bedke, T., Zazara, D. E., Zhao, L., Lücke, J., Sabihi, M., Fazio, A., Zhang, S., Tauriello, D. V. F., Batlle, E., Steglich, B., Kempski, J., Agalioti, T., Nawrocki, M., Xu, Y., Riecken, K., Liebold, I., Brockmann, L., ... Huber, S. (2024). IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction. J HEPATOL, 80(4), 634-644. https://doi.org/10.1016/j.jhep.2023.12.015

Vancouver

Shiri AM, Zhang T, Bedke T, Zazara DE, Zhao L, Lücke J et al. IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction. J HEPATOL. 2024 Apr;80(4):634-644. https://doi.org/10.1016/j.jhep.2023.12.015

Bibtex

@article{8523508e0f9d4d82a9cd1bfdcf528351,
title = "IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction",
abstract = "BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo.METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10.RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions.CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases.IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.",
author = "Shiri, {Ahmad Mustafa} and Tao Zhang and Tanja Bedke and Zazara, {Dimitra E} and Lilan Zhao and J{\"o}ran L{\"u}cke and Morsal Sabihi and Antonella Fazio and Siwen Zhang and Tauriello, {Daniele V F} and Eduard Batlle and Babett Steglich and Jan Kempski and Theodora Agalioti and Miko{\l}aj Nawrocki and Yang Xu and Kristoffer Riecken and Imke Liebold and Leonie Brockmann and Leonie Konczalla and Lidia Bosurgi and Baris Mercanoglu and Philipp Seeger and Natalie K{\"u}sters and Lykoudis, {Panagis M} and Asmus Heumann and Arck, {Petra C} and Boris Fehse and Philipp Busch and Rainer Grotel{\"u}schen and Oliver Mann and Izbicki, {Jakob R} and Thilo Hackert and Flavell, {Richard A} and Nicola Gagliani and Giannou, {Anastasios D} and Samuel Huber",
note = "Copyright {\textcopyright} 2023. Published by Elsevier B.V.",
year = "2024",
month = apr,
doi = "10.1016/j.jhep.2023.12.015",
language = "English",
volume = "80",
pages = "634--644",
journal = "J HEPATOL",
issn = "0168-8278",
publisher = "Elsevier",
number = "4",

}

RIS

TY - JOUR

T1 - IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction

AU - Shiri, Ahmad Mustafa

AU - Zhang, Tao

AU - Bedke, Tanja

AU - Zazara, Dimitra E

AU - Zhao, Lilan

AU - Lücke, Jöran

AU - Sabihi, Morsal

AU - Fazio, Antonella

AU - Zhang, Siwen

AU - Tauriello, Daniele V F

AU - Batlle, Eduard

AU - Steglich, Babett

AU - Kempski, Jan

AU - Agalioti, Theodora

AU - Nawrocki, Mikołaj

AU - Xu, Yang

AU - Riecken, Kristoffer

AU - Liebold, Imke

AU - Brockmann, Leonie

AU - Konczalla, Leonie

AU - Bosurgi, Lidia

AU - Mercanoglu, Baris

AU - Seeger, Philipp

AU - Küsters, Natalie

AU - Lykoudis, Panagis M

AU - Heumann, Asmus

AU - Arck, Petra C

AU - Fehse, Boris

AU - Busch, Philipp

AU - Grotelüschen, Rainer

AU - Mann, Oliver

AU - Izbicki, Jakob R

AU - Hackert, Thilo

AU - Flavell, Richard A

AU - Gagliani, Nicola

AU - Giannou, Anastasios D

AU - Huber, Samuel

N1 - Copyright © 2023. Published by Elsevier B.V.

PY - 2024/4

Y1 - 2024/4

N2 - BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo.METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10.RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions.CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases.IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

AB - BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo.METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10.RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions.CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases.IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

U2 - 10.1016/j.jhep.2023.12.015

DO - 10.1016/j.jhep.2023.12.015

M3 - SCORING: Journal article

C2 - 38160941

VL - 80

SP - 634

EP - 644

JO - J HEPATOL

JF - J HEPATOL

SN - 0168-8278

IS - 4

ER -