TY - JOUR
T1 - Tumor-associated macrophages respond to chemotherapy by detrimental transcriptional reprogramming and suppressing stabilin-1 mediated clearance of EGF
AU - Larionova, Irina
AU - Kiselev, Artem
AU - Kazakova, Elena
AU - Liu, Tengfei
AU - Patysheva, Marina
AU - Iamshchikov, Pavel
AU - Liu, Quan
AU - Mossel, Dieuwertje M.
AU - Riabov, Vladimir
AU - Rakina, Militsa
AU - Sergushichev, Alexey
AU - Bezgodova, Natalia
AU - Vtorushin, Sergei
AU - Litviakov, Nikolai
AU - Denisov, Evgeny
AU - Koshkin, Philipp
AU - Pyankov, Denis
AU - Tsyganov, Matvei
AU - Ibragimova, Marina
AU - Cherdyntseva, Nadezhda
AU - Kzhyshkowska, Julia
N1 - Publisher Copyright:
Copyright © 2023 Larionova, Kiselev, Kazakova, Liu, Patysheva, Iamshchikov, Liu, Mossel, Riabov, Rakina, Sergushichev, Bezgodova, Vtorushin, Litviakov, Denisov, Koshkin, Pyankov, Tsyganov, Ibragimova, Cherdyntseva and Kzhyshkowska.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - breast cancer
KW - cisplatin
KW - clearance
KW - EGF
KW - endocytosis
KW - stabilin-1
KW - tumor-associated macrophage (TAM)
UR - http://www.scopus.com/inward/record.url?scp=85150689754&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2023.1000497
DO - 10.3389/fimmu.2023.1000497
M3 - Article
C2 - 36960065
AN - SCOPUS:85150689754
SN - 1664-3224
VL - 14
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1000497
ER -