Tumor-associated macrophages (TAMs) are often associated with chemoresistance and resultant poor clinical outcome in solid tumors. Here, we demonstrated that TAMs-released chemokine-C-C motif chemokine 22 (CCL22) in esophageal squamous cell carcinoma (ESCC) stroma was tightly correlated with the chemoresistance of ESCC patients. TAMs-secreted CCL22 was able to block the growth inhibitory and apoptosis-promoting effects of cisplatin on ESCC cells. Mechanistically, CCL22 stimulated intratumoral diacylglycerol kinase α (DGKα) to produce phosphatidic acid (PA), which suppressed the activity of NADPH oxidase 4 (NOX4) and then blocked the overproduction of intratumoral reactive species oxygen (ROS) induced by cisplatin. CCL22 activated DGKα/nuclear factor-κB (NF-κB) axis to upregulate the level of several members of ATP binding cassette (ABC) transporter superfamily, including ABC sub-family G member 4 (ABCG4), ABC sub-family A member 3 (ABCA3), and ABC sub-family A member 5 (ABCA5), to lower the intratumoral concentration of cisplatin. Consequently, these processes induced the cisplatin resistance in ESCC cells. In xenografted models, targeting DGKα with 5’-cholesterol-conjugated small-interfering (si) RNA enhanced the chemosensitivity of cisplatin in ESCC treatment, especially in the context of TAMs. Our data establish the correlation between the TAMs-induced intratumoral metabolic product/ROS axis and chemotherapy efficacy in ESCC treatment and reveal relevant molecular mechanisms.

中文翻译：

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肿瘤相关巨噬细胞（TAM）分泌的CCL22通过调节二酰甘油激酶α（DGKα）/NOX4轴的活性赋予食管鳞状细胞癌（ESCC）细胞顺铂耐药性

肿瘤相关巨噬细胞（TAM）通常与实体瘤的化疗耐药性和由此导致的不良临床结果相关。在这里，我们证明食管鳞状细胞癌（ESCC）基质中TAMs释放的趋化因子-CC基序趋化因子22（CCL22）与ESCC患者的化疗耐药性密切相关。TAM 分泌的 CCL22 能够阻断顺铂对 ESCC 细胞的生长抑制和凋亡促进作用。从机制上讲，CCL22刺激瘤内二酰甘油激酶α（DGKα）产生磷脂酸（PA），磷脂酸（PA）抑制NADPH氧化酶4（NOX4）的活性，然后阻止顺铂诱导的瘤内活性氧（ROS）的过量产生。CCL22激活DGKα/核因子-κB（NF-κB）轴，上调ATP结合盒（ABC）转运蛋白超家族多个成员的水平，包括ABC亚家族G成员4（ABCG4）、ABC亚家族A成员3 (ABCA3) 和 ABC 亚家族 A 成员 5 (ABCA5)，以降低顺铂的瘤内浓度。因此，这些过程诱导了食管鳞癌细胞的顺铂耐药性。在异种移植模型中，用 5'-胆固醇缀合的小干扰 (si) RNA 靶向 DGKα 增强了 ESCC 治疗中顺铂的化疗敏感性，特别是在 TAM 的情况下。我们的数据建立了 TAM 诱导的瘤内代谢产物/ROS 轴与 ESCC 治疗中化疗疗效之间的相关性，并揭示了相关的分子机制。