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PreprintCited by 5Immune cells in cancerCancer Immunotherapy and BiomarkersTGF-β signaling in diseases

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Delineation of signaling routes that underlie differences in macrophage phenotypic states

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Totu, Tiberiu, Bossart, Jonas, Hast, Katharina, Li, Chen, Rottmar, Markus, Sobottka, Bettina, Yu, Guocan, Ayala-Nunez, Vanesa, Buljan, Marija·2024·NAR Molecular Medicine
DOI 10.1101/2024.01.12.574349PMC PMC12430007

Preprint — published as 10.1093/narmme/ugaf013

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Abstract

Macrophages represent a major immune cell type in tumor microenvironments, they exist in multiple functional states and are of a strong interest for therapeutic reprogramming. While signaling cascades defining pro-inflammatory macrophages are better characterized, pathways that drive polarization in immunosuppressive macrophages are incompletely mapped. Here, we performed an in-depth characterization of signaling events in primary human macrophages in different functional states using mass spectrometry-based proteomic and phosphoproteomic profiling. Analysis of direct and indirect footprints of kinase activities has suggested PAK2 and PKCα kinases as important regulators of in vitro immunosuppressive macrophages (IL-4/IL-13 or IL-10 stimulated). Network integration of these data with the corresesponding transcriptome profiles has further highlighted FOS and NCOR2 as central transcription regulators in immunosuppressive states. Furthermore, we retrieved single cell sequencing datasets for tumors from cancer patients and found that the unbiased signatures identified here through proteomic analysis were able to successfully separate pro-inflammatory macrophage populations in a clinical setting and could thus be used to expand state-specific markers. This study contributes to in-depth multi-omics characterizations of macrophage phenotypic landscapes, which could be valuable for assisting future interventions that therapeutically alter immune cell compartments. Abstract Figure: Highlights: Global proteomic characterization of primary human macrophages in different states Mapping of main signaling events through in-depth data analysis PKCα and PAK2 kinases are important regulators of immunosuppressive macrophages Proteomic signatures enable accurate detection of pro-inflammatory macrophages in patient tumors

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Metadata

Authors
Totu, T., Bossart, J., Hast, K., Li, C., Rottmar, M., Sobottka, B., Yu, G., Ayala-Nunez, V., & Buljan, M.
Affiliations
  • SIB Swiss Institute of Bioinformatics (CH)
  • Monash University (AU)
  • Empa (CH)
  • University of Zurich (CH)
  • Tsinghua University (CN)
Corresponding author
Buljan, Marija
ORCID
Venue
NAR Molecular Medicine
Publisher
openRxiv
Published
2024-01-14
Volume
2
Issue
2
Pages
ugaf013-ugaf013
ISSN
2976-856X (ISSN-L)
DOI
10.1101/2024.01.12.574349
PMC
PMC12430007
OpenAlex
W4409788561
Cited by
5
References
1
Citations by year
2026: 2 · 2025: 2 · 2024: 1
FWCI
1.48
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • NAR Molecular Medicine (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DORA Empa (Swiss Federal Laboratories for Materials Science and Technology (Empa)) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Cure Cancer Australia Foundation (CCAF2023)
  • Eidgenössische Technische Hochschule Zürich
  • Universität Zürich
  • Uniscientia Stiftung
  • Swiss Cancer Foundation
  • Medical Research Council
  • Australian Research Council (FT240100798)
  • National Health and Medical Research Council (2037597)
  • Functional Genomics Center Zurich
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
macrophage polarization, immunosuppressive macrophages, inflammatory macrophages, tumor microenvironment, signaling pathways, PAK2, protein kinase C alpha, FOS, NCOR2, transcriptional regulation, phosphoproteomics, kinase activity, single-cell transcriptomics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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