pancreatic ductal adenocarcinoma exomes in study: Pro-immunogenic Impact of MEK inhibition combined with an anti-CD40 immunostimulatory antibody

Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T-cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor resulted in potent synergistic anti-tumor efficacy. Detailed analysis of the mechanism of action of MEKi GDC-0623 by means of flow cytometric analysis of the tumor immune infiltrate and whole tumor transcriptomics showed that, in addition to its cytostatic impact on tumor cells, this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and CD4+ T-regulatory cells. In addition, MEKi was found to induce tumor-cell intrinsic interferon signaling, which contributed to antigen presentation by tumor cells. Finally, the tumoridical impact of MEKi involves the activation of multiple pro-inflammatory pathways involved in immune cell effector function in the tumor microenvironment. Our data therefore indicate that the combination of MEK inhibition with agonist anti-CD40 Ab is a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.
The pancreatic ductal adenocarcinoma exomes were generated in the context of the Heidelberg Center for Personalized Oncology project HIPO-K28E.EGA study EGAS00001004196

突变负荷较低且肿瘤微环境（tumor microenvironment, TME）呈非允许型的癌症类型，其本身对免疫检查点阻断（immune checkpoint blockade）治疗具有固有耐药性。尽管细胞生长抑制药物与免疫刺激性抗体的联合疗法是克服该耐药性的极具吸引力的治疗策略，但细胞生长抑制药物对免疫细胞功能的抑制作用可能会限制治疗效果。本研究证实，靶向抑制丝裂原活化蛋白激酶激酶（mitogen-activated protein kinase kinase, MEK）并不会损害树突状细胞（dendritic cell, DC）介导的T细胞致敏与活化过程。因此，将MEK抑制剂（MEK inhibitors, MEKi）与靶向免疫刺激性CD40受体的激动剂抗体（agonist antibodies, Abs）联合使用，可产生强效的协同抗肿瘤效应。通过对肿瘤免疫浸润细胞进行流式细胞术分析以及全肿瘤转录组学分析，对MEKi GDC-0623的作用机制展开详细解析后发现，该药物除了对肿瘤细胞产生细胞生长抑制作用外，还可发挥多种促免疫原性效应，包括抑制M2型巨噬细胞、髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）以及CD4+调节性T细胞。此外，研究发现MEKi可诱导肿瘤细胞固有的干扰素信号通路活化，从而促进肿瘤细胞的抗原呈递过程。最终，MEKi的抗肿瘤活性还可通过激活肿瘤微环境中参与免疫细胞效应功能的多条促炎通路来实现。综上，本研究数据表明，MEK抑制与抗CD40激动剂抗体联合的治疗策略极具应用前景，尤其适用于突变Kras驱动的肿瘤，如胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）。
本研究中的胰腺导管腺癌外显子组数据，是在海德堡个性化肿瘤学中心HIPO-K28E项目以及欧洲基因组表型档案（European Genome-phenome Archive, EGA）的EGAS00001004196研究框架下生成的。