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.
Front Immunol. 2023 Mar 7;14:1000497. doi: 10.3389/fimmu.2023.1000497. eCollection 2023.
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.
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.
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.
Our data demonstrate that synergistic action of cytostatic agents and innovative immunomodulators is required to overcome cancer therapy resistance.
肿瘤对化疗的耐药性和转移性复发导致了 90%以上的癌症特异性死亡。肿瘤相关巨噬细胞（TAMs）可以处理化疗药物并削弱其作用。然而，人们对化疗药物对 TAMs 的直接影响知之甚少。
在人离体 TAMs 模型系统中评估化疗铂剂顺铂的作用。通过 NGS 分析顺铂刺激和未刺激的配对 TAMs 的全转录组测序。通过流式细胞术定量测定 EGF 的内吞作用。利用共聚焦显微镜观察在表达异位重组稳定素-1的 CHO 细胞和稳定素-1+TAMs 中 EGF 的稳定素-1 介导的内化和内吞运输。在乳腺癌患者队列中，验证了铂类治疗对 TAMs 转录组的影响，并确定了内吞作用调节因子的差异表达。
我们发现化疗药物顺铂可以在不显著损害 TAMs 活力的情况下，启动 TAMs 有害的转录和功能程序。我们专注于 TAMs 的清除功能，该功能控制肿瘤微环境的组成。我们首次证明 TAMs 的清道夫受体稳定素-1负责清除表皮生长因子（EGF），EGF 是一种促进肿瘤生长的有效刺激物。顺铂通过双向模式抑制 TAMs 的总体和 EGF 特异性内吞作用：抑制内吞作用的正向调节因子和刺激负向调节因子，对突触结合蛋白 11（SYT11）的抑制作用最强，在乳腺癌患者中得到了证实。
我们的数据表明，需要细胞毒药物和创新免疫调节剂的协同作用来克服癌症治疗耐药性。
