Tumor-associated macrophages respond to chemotherapy by detrimental transcriptional reprogramming and suppressing stabilin-1 mediated clearance of EGF.

Autor:	Larionova I; Laboratory of translational cellular and molecular biomedicine, National Research Tomsk State University, Tomsk, Russia.; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.; Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia., Kiselev A; Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI, United States., Kazakova E; Laboratory of translational cellular and molecular biomedicine, National Research Tomsk State University, Tomsk, Russia.; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Liu T; Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Patysheva M; Laboratory of translational cellular and molecular biomedicine, National Research Tomsk State University, Tomsk, Russia.; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Iamshchikov P; Laboratory of translational cellular and molecular biomedicine, National Research Tomsk State University, Tomsk, Russia.; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Liu Q; Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Mossel DM; Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Riabov V; Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany., Rakina M; Laboratory of translational cellular and molecular biomedicine, National Research Tomsk State University, Tomsk, Russia.; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Sergushichev A; Saint Petersburg National Research University of Information Technologies, Mechanics and Optics (ITMO University), Saint Petersburg, Russia., Bezgodova N; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Vtorushin S; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Litviakov N; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.; Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia., Denisov E; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Koshkin P; Laboratory of Molecular Pathology, Genomed, Moscow, Russia., Pyankov D; Laboratory of Molecular Pathology, Genomed, Moscow, Russia., Tsyganov M; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Ibragimova M; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Cherdyntseva N; Laboratory of translational cellular and molecular biomedicine, National Research Tomsk State University, Tomsk, Russia.; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.; Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia., Kzhyshkowska J; Laboratory of translational cellular and molecular biomedicine, National Research Tomsk State University, Tomsk, Russia.; Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia.; Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.; German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Mar 07; Vol. 14, pp. 1000497. Date of Electronic Publication: 2023 Mar 07 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1000497
Abstrakt:	Introduction: Tumor resistance to chemotherapy and metastatic relapse account for more than 90% of cancer specific mortality. Tumor-associated macrophages (TAMs) can process chemotherapeutic agents and impair their action. Little is known about the direct effects of chemotherapy on TAMs. Methods: The effect of chemotherapeutic platinum agent cisplatin was assessed in the model system of human ex vivo TAMs. Whole-transcriptome sequencing for paired TAMs stimulated and not stimulated by cisplatin was analysed by NGS. Endocytic uptake of EGF was quantified by flow cytometry. Confocal microscopy was used to visualize stabilin-1-mediated internalization and endocytic trafficking of EGF in CHO cells expressing ectopically recombinant stabilin-1 and in stabilin-1+ TAMs. In cohort of patients with breast cancer, the effect of platinum therapy on the transcriptome of TAMs was validated, and differential expression of regulators of endocytosis was identified. Results: Here we show that chemotherapeutic agent cisplatin can initiate detrimental transcriptional and functional programs in TAMs, without significant impairment of their viability. We focused on the clearance function of TAMs that controls composition of tumor microenvironment. For the first time we demonstrated that TAMs' scavenger receptor stabilin-1 is responsible for the clearance of epidermal growth factor (EGF), a potent stimulator of tumor growth. Cisplatin suppressed both overall and EGF-specific endocytosis in TAMs by bidirectional mode: suppression of positive regulators and stimulation of negative regulators of endocytosis, with strongest effect on synaptotagmin-11 (SYT11), confirmed in patients with breast cancer. Conclusion: Our data demonstrate that synergistic action of cytostatic agents and innovative immunomodulators is required to overcome cancer therapy resistance. Competing Interests: Authors DP and PK were employed by company Genomed. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Larionova, Kiselev, Kazakova, Liu, Patysheva, Iamshchikov, Liu, Mossel, Riabov, Rakina, Sergushichev, Bezgodova, Vtorushin, Litviakov, Denisov, Koshkin, Pyankov, Tsyganov, Ibragimova, Cherdyntseva and Kzhyshkowska.)
Databáze:	MEDLINE
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