Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity

Lukas M. Braun; Sophie Giesler; Geoffroy Andrieux; Roxane Riemer; Nana Talvard-Balland; Sandra Duquesne; Tamina Rückert; Susanne Unger; Stefanie Kreutmair; Melissa Zwick; Marie Follo; Alina Hartmann; Natascha Osswald; Wolfgang Melchinger; Stefanie Chapman; James A. Hutchinson; Sebastian Haferkamp; Leopold Torster; Julian Kött; Christoffer Gebhardt; Dirk Hellwig; Nikolaos Karantzelis; Till Wallrabenstein; Theresa Lowinus; Mehtap Yücel; Niklas Brehm; Justyna Rawluk; Dietmar Pfeifer; Peter Bronsert; Manuel Rogg; Sven Mattern; Mathias Heikenwälder; Stefano Fusco; Nisar P. Malek; Stephan Singer; Annette Schmitt-Graeff; Fatih Ceteci; Florian R. Greten; Bruce R. Blazar; Melanie Boerries; Natalie Köhler; Justus Duyster; Gabriele Ihorst; Silke Lassmann; Philip Keye; Susana Minguet; Dirk Schadendorf; Selma Ugurel; David Rafei-Shamsabadi; Robert Thimme; Peter Hasselblatt; Bertram Bengsch; Christoph Schell; Erika L. Pearce; Frank Meiss; Burkhard Becher; Carolin Funke-Lorenz; Jan Malte Placke; Petya Apostolova; Robert Zeiser

doi:10.1016/j.ccell.2025.01.004

Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity

Lukas M. Braun
, Sophie Giesler
, Geoffroy Andrieux
, Roxane Riemer
, Nana Talvard-Balland
, Sandra Duquesne
, Tamina Rückert
, Susanne Unger
, Stefanie Kreutmair
, Melissa Zwick
, Marie Follo
, Alina Hartmann
, Natascha Osswald
, Wolfgang Melchinger
, Stefanie Chapman
, James A. Hutchinson
, Sebastian Haferkamp
, Leopold Torster
, Julian Kött
, Christoffer Gebhardt

Dirk Hellwig, Nikolaos Karantzelis, Till Wallrabenstein, Theresa Lowinus, Mehtap Yücel, Niklas Brehm, Justyna Rawluk, Dietmar Pfeifer, Peter Bronsert, Manuel Rogg, Sven Mattern, Mathias Heikenwälder, Stefano Fusco, Nisar P. Malek, Stephan Singer, Annette Schmitt-Graeff, Fatih Ceteci, Florian R. Greten, Bruce R. Blazar, Melanie Boerries, Natalie Köhler, Justus Duyster, Gabriele Ihorst, Silke Lassmann, Philip Keye, Susana Minguet, Dirk Schadendorf, Selma Ugurel, David Rafei-Shamsabadi, Robert Thimme, Peter Hasselblatt, Bertram Bengsch, Christoph Schell, Erika L. Pearce, Frank Meiss, Burkhard Becher, Carolin Funke-Lorenz, Jan Malte Placke, Petya Apostolova, Robert Zeiser

School of Medicine

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

Abstract

Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%–99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%–100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4⁺IFN-γ⁺ T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.

Original language	English (US)
Pages (from-to)	269-291.e19
Journal	Cancer cell
Volume	43
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2025.01.004
State	Published - Feb 10 2025

Keywords

adiponectin
anti-tumor immunity
arginase-1
cancer immunotherapy
colitis
extracorporeal photopheresis
immune checkpoint inhibition
immune-related adverse events
immunomodulation
immunosuppression

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2025.01.004

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Braun, L. M., Giesler, S., Andrieux, G., Riemer, R., Talvard-Balland, N., Duquesne, S., Rückert, T., Unger, S., Kreutmair, S., Zwick, M., Follo, M., Hartmann, A., Osswald, N., Melchinger, W., Chapman, S., Hutchinson, J. A., Haferkamp, S., Torster, L., Kött, J., ... Zeiser, R. (2025). Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity. Cancer cell, 43(2), 269-291.e19. https://doi.org/10.1016/j.ccell.2025.01.004

Braun, LM, Giesler, S, Andrieux, G, Riemer, R, Talvard-Balland, N, Duquesne, S, Rückert, T, Unger, S, Kreutmair, S, Zwick, M, Follo, M, Hartmann, A, Osswald, N, Melchinger, W, Chapman, S, Hutchinson, JA, Haferkamp, S, Torster, L, Kött, J, Gebhardt, C, Hellwig, D, Karantzelis, N, Wallrabenstein, T, Lowinus, T, Yücel, M, Brehm, N, Rawluk, J, Pfeifer, D, Bronsert, P, Rogg, M, Mattern, S, Heikenwälder, M, Fusco, S, Malek, NP, Singer, S, Schmitt-Graeff, A, Ceteci, F, Greten, FR, Blazar, BR, Boerries, M, Köhler, N, Duyster, J, Ihorst, G, Lassmann, S, Keye, P, Minguet, S, Schadendorf, D, Ugurel, S, Rafei-Shamsabadi, D, Thimme, R, Hasselblatt, P, Bengsch, B, Schell, C, Pearce, EL, Meiss, F, Becher, B, Funke-Lorenz, C, Placke, JM, Apostolova, P & Zeiser, R 2025, 'Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity', Cancer cell, vol. 43, no. 2, pp. 269-291.e19. https://doi.org/10.1016/j.ccell.2025.01.004

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title = "Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity",

abstract = "Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92\% (95\% confidence interval [CI]: 63.97\%–99.81\%); colitis-specific complete remission rate is 100\% (95\% CI: 63.06\%–100\%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4+IFN-γ+ T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.",

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author = "Braun, \{Lukas M.\} and Sophie Giesler and Geoffroy Andrieux and Roxane Riemer and Nana Talvard-Balland and Sandra Duquesne and Tamina R{\"u}ckert and Susanne Unger and Stefanie Kreutmair and Melissa Zwick and Marie Follo and Alina Hartmann and Natascha Osswald and Wolfgang Melchinger and Stefanie Chapman and Hutchinson, \{James A.\} and Sebastian Haferkamp and Leopold Torster and Julian K{\"o}tt and Christoffer Gebhardt and Dirk Hellwig and Nikolaos Karantzelis and Till Wallrabenstein and Theresa Lowinus and Mehtap Y{\"u}cel and Niklas Brehm and Justyna Rawluk and Dietmar Pfeifer and Peter Bronsert and Manuel Rogg and Sven Mattern and Mathias Heikenw{\"a}lder and Stefano Fusco and Malek, \{Nisar P.\} and Stephan Singer and Annette Schmitt-Graeff and Fatih Ceteci and Greten, \{Florian R.\} and Blazar, \{Bruce R.\} and Melanie Boerries and Natalie K{\"o}hler and Justus Duyster and Gabriele Ihorst and Silke Lassmann and Philip Keye and Susana Minguet and Dirk Schadendorf and Selma Ugurel and David Rafei-Shamsabadi and Robert Thimme and Peter Hasselblatt and Bertram Bengsch and Christoph Schell and Pearce, \{Erika L.\} and Frank Meiss and Burkhard Becher and Carolin Funke-Lorenz and Placke, \{Jan Malte\} and Petya Apostolova and Robert Zeiser",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = feb,

day = "10",

doi = "10.1016/j.ccell.2025.01.004",

language = "English (US)",

volume = "43",

pages = "269--291.e19",

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T1 - Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity

AU - Braun, Lukas M.

AU - Giesler, Sophie

AU - Andrieux, Geoffroy

AU - Riemer, Roxane

AU - Talvard-Balland, Nana

AU - Duquesne, Sandra

AU - Rückert, Tamina

AU - Unger, Susanne

AU - Kreutmair, Stefanie

AU - Zwick, Melissa

AU - Follo, Marie

AU - Hartmann, Alina

AU - Osswald, Natascha

AU - Melchinger, Wolfgang

AU - Chapman, Stefanie

AU - Hutchinson, James A.

AU - Haferkamp, Sebastian

AU - Torster, Leopold

AU - Kött, Julian

AU - Gebhardt, Christoffer

AU - Hellwig, Dirk

AU - Karantzelis, Nikolaos

AU - Wallrabenstein, Till

AU - Lowinus, Theresa

AU - Yücel, Mehtap

AU - Brehm, Niklas

AU - Rawluk, Justyna

AU - Pfeifer, Dietmar

AU - Bronsert, Peter

AU - Rogg, Manuel

AU - Mattern, Sven

AU - Heikenwälder, Mathias

AU - Fusco, Stefano

AU - Malek, Nisar P.

AU - Singer, Stephan

AU - Schmitt-Graeff, Annette

AU - Ceteci, Fatih

AU - Greten, Florian R.

AU - Blazar, Bruce R.

AU - Boerries, Melanie

AU - Köhler, Natalie

AU - Duyster, Justus

AU - Ihorst, Gabriele

AU - Lassmann, Silke

AU - Keye, Philip

AU - Minguet, Susana

AU - Schadendorf, Dirk

AU - Ugurel, Selma

AU - Rafei-Shamsabadi, David

AU - Thimme, Robert

AU - Hasselblatt, Peter

AU - Bengsch, Bertram

AU - Schell, Christoph

AU - Pearce, Erika L.

AU - Meiss, Frank

AU - Becher, Burkhard

AU - Funke-Lorenz, Carolin

AU - Placke, Jan Malte

AU - Apostolova, Petya

AU - Zeiser, Robert

PY - 2025/2/10

Y1 - 2025/2/10

N2 - Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%–99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%–100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4+IFN-γ+ T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.

AB - Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%–99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%–100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4+IFN-γ+ T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.

KW - adiponectin

KW - anti-tumor immunity

KW - arginase-1

KW - cancer immunotherapy

KW - colitis

KW - extracorporeal photopheresis

KW - immune checkpoint inhibition

KW - immune-related adverse events

KW - immunomodulation

KW - immunosuppression

UR - https://www.scopus.com/pages/publications/85216994677

UR - https://www.scopus.com/pages/publications/85216994677#tab=citedBy

U2 - 10.1016/j.ccell.2025.01.004

DO - 10.1016/j.ccell.2025.01.004

M3 - Article

C2 - 39933899

AN - SCOPUS:85216994677

SN - 1535-6108

VL - 43

SP - 269-291.e19

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -

Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity

Abstract

Keywords

ASJC Scopus subject areas

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