Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.

了解突变型 KRAS 肺癌中靶向治疗和免疫检查点阻断的耐药机制对于开发新型联合疗法和提高患者存活率至关重要。在这里，我们表明 MEK 抑制增强了 PD-L1 表达，而 PD-L1 阻断上调了突变型 KRAS 肺肿瘤中的 MAPK 信号传导。将 MEK 抑制与抗 PD-L1 结合可协同减少肺肿瘤的生长和转移，但肿瘤最终对持续组合治疗产生抗性。多平台分析显示，耐药性肺肿瘤增加了 Th17 细胞的浸润，Th17 细胞分泌 IL-17 和 IL-22 细胞因子，促进肺癌细胞侵袭性和 MEK 抑制剂耐药性。IL-17A 的抗体消耗结合 MEK 抑制和 PD-L1 阻断显着降低了体内治疗耐药性。在临床上，接受 PD-1 阻断剂治疗的患者中 Th17 相关基因表达的增加预测黑色素瘤的总体生存率和反应较差，并预测 NSCLC 患者对抗 PD1 的反应较差。在这里，我们展示了一种三重组合治疗策略，以克服对组合 MEK 抑制剂和 PD-L1 阻断的耐药性。