肺癌是全球癌症相关死亡的主要原因，然而，对化疗药物的耐药性仍然是有效治疗的巨大障碍。化疗后骨髓源性抑制细胞（MDSC）向肿瘤的募集增加与化疗药物的耐药性有关。尽管如此，具体机制仍不清楚。 oxPAPC 是最低限度修饰的低密度脂蛋白的生物活性主要成分，可调节炎症反应。在这项工作中，我们发现顺铂、奥沙利铂和 ADM 都会增加肿瘤中 oxPAPC 的释放。在体外用 oxPAPC 处理巨噬细胞会刺激 MCP-1 和 LTB4 的分泌，分别强烈诱导单核细胞和中性粒细胞的趋化性。体内注射 oxPAPC 显着上调野生型 LL2 荷瘤小鼠肿瘤微环境 (TME) 中 MDSC 的百分比，但不影响 CCL2-/- 小鼠和 LTB4R-/- 小鼠。至关重要的是，oxPAPC 在 LL2 肿瘤模型中充当促肿瘤因子。事实上，顺铂增加了WT小鼠、CCL2-/-和LTB4R-/-小鼠肿瘤组织中的oxPAPC水平，但仅在携带LL2的WT小鼠中引起Ly6Chigh单核细胞和中性粒细胞浸润增加。总的来说，我们的工作表明顺铂治疗会诱导 oxPAPC 过量产生，从而招募 MDSC 浸润，通过 MCP-1/CCL2 和 LTB4/LTB4R 途径促进肿瘤生长，这可能会限制多种化疗的效果。这为通过靶向 oxPAPC 来增强多种化疗药物治疗肺癌的疗效的潜在策略提供了证据。© 2023 作者。北京干细胞与再生医学研究院和John Wiley联合出版的《细胞增殖》

Lung cancer is the leading global cause of cancer-related death, however, resistance to chemotherapy drugs remains a huge barrier to effective treatment. The elevated recruitment of myeloid derived suppressor cells (MDSCs) to tumour after chemotherapy has been linked to resistance of chemotherapy drugs. Nevertheless, the specific mechanism remains unclear. oxPAPC is a bioactive principal component of minimally modified low-density lipoproteins and regulates inflammatory response. In this work, we found that cisplatin, oxaliplatin and ADM all increased oxPAPC release in tumour. Treating macrophages with oxPAPC in vitro stimulated the secretion of MCP-1 and LTB4, which strongly induced monocytes and neutrophils chemotaxis, respectively. Injection of oxPAPC in vivo significantly upregulated the percentage of MDSCs in tumour microenvironment (TME) of wild-type LL2 tumour-bearing mice, but not CCL2-/- mice and LTB4R-/- mice. Critically, oxPAPC acted as a pro-tumor factor in LL2 tumour model. Indeed, cisplatin increased oxPAPC level in tumour tissues of WT mice, CCL2-/- and LTB4R-/- mice, but caused increased infiltration of Ly6Chigh monocytes and neutrophils only in WT LL2-bearing mice. Collectively, our work demonstrates cisplatin treatment induces an overproduction of oxPAPC and thus recruits MDSCs infiltration to promote the tumour growth through the MCP-1/CCL2 and LTB4/LTB4R pathways, which may restrict the effect of multiple chemotherapy. This provides evidence for a potential strategy to enhance the efficacy of multiple chemotherapeutic drugs in the treatment of lung cancer by targeting oxPAPC.© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.