A macrophage-predominant immunosuppressive microenvironment and therapeutic vulnerabilities in advanced salivary gland cancer

Erika Zuljan, Benjamin Emde, Iris Piwonski, Ana Pestana, Konrad Klinghammer, Andreas Mock, Peter Horak, Christoph Heining, Frederick Klauschen, Ina Pretzell, Melanie Boerries, Christian H. Brandts, Simon Kreutzfeldt, Maria-Veronica Teleanu, Daniel Hübschmann, Luc G. T. Morris, Max Heiland, Ulrich Keller, Thomas Conrad, Hanno Glimm, Stefan Fröhling, Sebastian Ochsenreither, Ulrich Keilholz, Eric Blanc, Dieter Beule and Damian T. Rieke ()
Additional contact information
Erika Zuljan: Berlin Institute of Health at Charité–Universitätsmedizin Berlin
Benjamin Emde: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Iris Piwonski: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Ana Pestana: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Konrad Klinghammer: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Andreas Mock: core center Heidelberg
Peter Horak: core center Heidelberg
Christoph Heining: and Helmholtz-Zentrum Dresden - Rossendorf (HZDR)
Frederick Klauschen: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Ina Pretzell: West German Cancer Center
Melanie Boerries: University of Freiburg
Christian H. Brandts: Hematology/Oncology & University Cancer Center Frankfurt (UCT)
Simon Kreutzfeldt: core center Heidelberg
Maria-Veronica Teleanu: core center Heidelberg
Daniel Hübschmann: core center Heidelberg
Luc G. T. Morris: Memorial Sloan Kettering Cancer Center
Max Heiland: BIH and MDC
Ulrich Keller: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Thomas Conrad: Berlin Institute of Health at Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Hanno Glimm: and Helmholtz-Zentrum Dresden - Rossendorf (HZDR)
Stefan Fröhling: core center Heidelberg
Sebastian Ochsenreither: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Ulrich Keilholz: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Eric Blanc: Berlin Institute of Health at Charité–Universitätsmedizin Berlin
Dieter Beule: Berlin Institute of Health at Charité–Universitätsmedizin Berlin
Damian T. Rieke: Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Salivary gland cancers are rare, diverse malignancies characterized by poor response to immunotherapy. The tumor immune environment in these cancers remains poorly understood. To address this, we perform an integrative analysis of the tumor immune microenvironment in a large cohort of advanced salivary gland cancer samples. Most tumors exhibit low immune activity with limited immune cell infiltration. Inflammation is linked to higher tumor mutational burden in non-adenoid cystic carcinoma histologies. Subtype specific expression of immune checkpoints is identified with prominent expression of VTCN1 in luminal-like cells within adenoid cystic carcinoma. Macrophages with immunosuppressive properties dominate the immune microenvironment across subtypes. Responses to immunotherapy are limited and associated with a higher ratio of T-cells relative to macrophages in individual cases, warranting further investigation. Here, we show an immunosuppressive environment in salivary gland cancers and identify subtype-specific immune vulnerabilities that could inform tailored therapeutic strategies.

Date: 2025
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DOI: 10.1038/s41467-025-60421-0

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