PIM kinase inhibition attenuates pro-tumoral and immunosuppressive functions of macrophages in classic Hodgkin lymphoma

Tumor-associated macrophages (TAMs) of classic Hodgkin Lymphoma (cHL) contribute to the development of immunosuppressive tumor microenvironment (TME) and are associated with worse treatment outcomes. However, detailed features, functions and therapeutic vulnerabilities of cHL TAMs remain largely unknown. To address this, we analyzed cHL diagnostic biopsies by Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and assessed transcriptional, proteomic and metabolic profiles of in vitro TAM models. We show that Reed-Sternberg (RS) cells induce a disease-specific TAM phenotype, characterized by elevated expression of factors involved in chemotaxis, angiogenesis, extracellular matrix remodeling and tumor immune escape. RS cell-conditioned TAMs expressed TGFβ, CCL17 and tryptophan catabolizing enzymes, IDO1 and IL4I1, promoting regulatory T cell recruitment and activation. In addition, we identified the expression of PIM1/2/3 kinases in cHL TAMs and characterized PIMs as critical hubs orchestrating RS-macrophage interactions. Pharmacological PIM blockade attenuated the RS-induced TAM transcriptional program. In established TAMs, PIM inhibition or PROTAC-mediated degradation decreased the expression of multiple factors associated with pro-tumoral TAM functions, including IL8, MMP9, CHI3L1/2, CD206, CD209, PD-L1, CCL17, TGFβ, IL4I1 and IDO1. PIM blockade attenuated TAM-dependent eosinophil chemoattraction, extracellular matrix remodeling, angiogenesis and regulatory T-cell development. Taken together, our study highlights the role of PIMs in the regulation of pathogenic TAM functions in cHL, further supporting the rationale of PIM targeting in this disease.

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Journal
Cell Death and Disease
Published
2025-12-26
DOI
https://doi.org/10.1038/s41419-025-08402-5
Citations
1
Primary Topic
Cancer Mechanisms and Therapy
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article
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1.47
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article

PIM kinase inhibition attenuates pro-tumoral and immunosuppressive functions of macrophages in classic Hodgkin lymphoma

Ewa Kurtz, Marcin Kaszkowiak, Jan Maciej Zaucha, Wojciech Kukwa et al.
1 citations
Cell Death and Disease
Cancer Mechanisms and Therapy
1.47
article

PIM kinase inhibition attenuates pro-tumoral and immunosuppressive functions of macrophages in classic Hodgkin lymphoma

Ewa Kurtz, Marcin Kaszkowiak, Jan Maciej Zaucha, Wojciech Kukwa, Paweł Wołkow, Maciej Szydłowski, Zofia Pilch, Patryk Górniak, Olga Szymańska-Giemza, Michał Kurlapski, Grzegorz Rymkiewicz, Ewa Lech-Maranda, John Brognard, Przemysław Juszczyński, Filip Garbicz, Alicja Braczko, Katarzyna Wiktorska, Sylwia Radomska, Natalia Ochocka, M. Prochorec-Sobieszek, Michał Pawlak, Marcin Tabaka, Julia Maroszek, Justyna Totoń-Żurańska, Dominika Nowis, Agnieszka Kołkowska-Leśniak, Jakub Golab, Anna Szumera-Ciećkiewicz, Ewa Paszkiewicz-Kozik, Sabina Lichołai
article en
1 citations

Abstract

Tumor-associated macrophages (TAMs) of classic Hodgkin Lymphoma (cHL) contribute to the development of immunosuppressive tumor microenvironment (TME) and are associated with worse treatment outcomes. However, detailed features, functions and therapeutic vulnerabilities of cHL TAMs remain largely unknown. To address this, we analyzed cHL diagnostic biopsies by Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and assessed transcriptional, proteomic and metabolic profiles of in vitro TAM models. We show that Reed-Sternberg (RS) cells induce a disease-specific TAM phenotype, characterized by elevated expression of factors involved in chemotaxis, angiogenesis, extracellular matrix remodeling and tumor immune escape. RS cell-conditioned TAMs expressed TGFβ, CCL17 and tryptophan catabolizing enzymes, IDO1 and IL4I1, promoting regulatory T cell recruitment and activation. In addition, we identified the expression of PIM1/2/3 kinases in cHL TAMs and characterized PIMs as critical hubs orchestrating RS-macrophage interactions. Pharmacological PIM blockade attenuated the RS-induced TAM transcriptional program. In established TAMs, PIM inhibition or PROTAC-mediated degradation decreased the expression of multiple factors associated with pro-tumoral TAM functions, including IL8, MMP9, CHI3L1/2, CD206, CD209, PD-L1, CCL17, TGFβ, IL4I1 and IDO1. PIM blockade attenuated TAM-dependent eosinophil chemoattraction, extracellular matrix remodeling, angiogenesis and regulatory T-cell development. Taken together, our study highlights the role of PIMs in the regulation of pathogenic TAM functions in cHL, further supporting the rationale of PIM targeting in this disease.

Cell Death and DiseaseVol. 17(1)
Broad Institute (US), Jagiellonian University (PL), Warsaw University of Life Sciences (PL), Medical University of Warsaw (PL), Instytut Hematologii i Transfuzjologi (PL), National Institute of Oncology (HU), Postgraduate School of Molecular Medicine (PL), National Cancer Institute (US), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Institute of Physical Chemistry (PL), Massachusetts Institute of Technology (US), Gdańsk Medical University (PL), University of Rzeszów (PL), Polish Academy of Sciences (PL)
Good health and well-being
Openalex Percentile: Top 13%
Cancer Mechanisms and Therapy
1.47
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