Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Perlmutter Cancer Center, NYU Langone Health, 550 First Avenue, Smilow Building 10th Floor, Suite 1010, New York, NY, USA.
Nat Commun. 2021 May 10;12(1):2606. doi: 10.1038/s41467-021-22875-w.
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.
了解靶向治疗和免疫检查点阻断在突变型 KRAS 肺癌中的耐药机制对于开发新的联合治疗方法和提高患者生存率至关重要。在这里，我们表明 MEK 抑制增强了 PD-L1 的表达，而 PD-L1 阻断上调了突变型 KRAS 肺肿瘤中的 MAPK 信号。MEK 抑制与抗 PD-L1 联合使用可协同减少肺肿瘤的生长和转移，但肿瘤最终对持续的联合治疗产生耐药性。多平台分析显示，耐药性肺肿瘤中 Th17 细胞浸润增加，这些细胞分泌 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。抗 IL-17A 抗体耗竭与 MEK 抑制和 PD-L1 阻断联合使用，显著减少了体内的治疗耐药性。临床上，接受 PD-1 阻断治疗的患者中 Th17 相关基因的表达增加预示着黑色素瘤患者的总生存率和反应较差，并且预示着 NSCLC 患者对抗 PD1 的反应较差。在这里，我们展示了一种克服 MEK 抑制剂和 PD-L1 阻断联合治疗耐药性的三联组合治疗策略。
