MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells [France3]. MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells [France3]

Chemotherapy with anti PD-1/PD-L1 mAb has become the standard of care for patients with metastatic non-small cell lung cancer (NSCLC). Using lung tumor models, where pemetrexed-platinum chemotherapy (PEM/CDDP) remains unable to synergize with immune checkpoint inhibitors (ICI), we linked failure of this treatment with its inability to induce CXCL10 expression and CD8+ T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8+ T cell recruitment, and restores ICI efficacy. PEM/CDDP plus MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA and TLR9-dependent manner. TLR9 or autophagy/mitophagy processes genetic inactivation of abort the antitumor efficacy of PEM/CDDP plus MEKi/anti PD-L1 therapy. In human NSCLC, high OPTN, TLR9 and CXCL10 expression is associated with better response to ICI. Our results underline the role of TLR9 and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy. Overall design: This advanced non-small cell lung cancer (NSCLC) cohort comprises patients treated with anti-PD1 therapy in first or second line as monotherapy at the Centre Georges-François Leclerc in Dijon (France #3), and is composed of 35 patients. Tumors were collected at diagnosis, stored, and used with the written informed consent of the patients and RNAseq data was generated in our NGS core facility. Raw data were pseudo-aligned and gene counts were quantified using the kallisto software. Clinical data were collected by Prof. F. Ghiringhelli.

抗PD-1/PD-L1单克隆抗体（anti PD-1/PD-L1 mAb）联合化疗已成为转移性非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的标准治疗方案。本研究针对培美曲塞联合铂类化疗（pemetrexed-platinum chemotherapy, PEM/CDDP）无法与免疫检查点抑制剂（immune checkpoint inhibitors, ICI）产生协同作用的肺癌模型，发现该治疗方案的失效与其无法诱导CXCL10表达以及CD8+T细胞招募密切相关。通过药物筛选实验，我们证实将MEK抑制剂（MEK inhibitor, MEKi）与PEM/CDDP联合使用，可触发癌细胞分泌CXCL10并招募CD8+T细胞，同时恢复免疫检查点抑制剂的抗肿瘤疗效。
PEM/CDDP联合MEKi可促进视神经蛋白（optineurin, OPTN）依赖的线粒体自噬（mitophagy），进而通过线粒体DNA（mitochondrial DNA）与Toll样受体9（Toll-like receptor 9, TLR9）依赖的途径诱导CXCL10产生。若TLR9或自噬/线粒体自噬通路发生遗传失活，则会阻断PEM/CDDP联合MEKi/抗PD-L1治疗的抗肿瘤效果。在人类NSCLC样本中，高表达OPTN、TLR9及CXCL10与患者对ICI的更佳临床应答相关。本研究结果明确了TLR9与OPTN依赖的线粒体自噬在增强化学免疫治疗疗效中的关键作用。
**总体实验设计**：本晚期非小细胞肺癌队列纳入了法国第戎乔治-弗朗索瓦·勒克莱尔中心（法国#3）接受一线或二线抗PD-1单药治疗的患者，共计35例。肿瘤样本于诊断时采集并保存，所有实验操作均获得患者书面知情同意；RNA测序（RNA-seq）数据在本中心下一代测序（next-generation sequencing, NGS）核心平台完成生成。原始测序数据通过kallisto软件进行伪比对并定量基因计数。临床数据由F. Ghiringhelli教授收集整理。