Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer.
Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer.
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DOI：
10.1136/gutjnl-2020-321000
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发表时间：
2021-01
期刊：
影响因子：
24.5
通讯作者：
Witkiewicz AK
中科院分区：
文献类型：
--
作者：
Knudsen ES;Kumarasamy V;Chung S;Ruiz A;Vail P;Tzetzo S;Wu J;Nambiar R;Sivinski J;Chauhan SS;Seshadri M;Abrams SI;Wang J;Witkiewicz AK
这项研究利用分子靶向治疗和免疫检查点抑制之间的交叉点来定义治疗胰腺癌的新方法。使用患者来源的细胞系和异种移植模型来确定肿瘤隔室中对CDK4/6和MEK抑制的反应。使用皮下和原位同基因模型进行相对于免疫治疗的影响。采用单细胞RNA测序和多光谱成像来描绘对肿瘤微环境中免疫环境的影响。我们发现，MEK和CDK4/6抑制剂的联合治疗在广泛的PDX模型中有效延缓肿瘤进展。这些效应与稳定的细胞周期阻滞以及诱导与干扰素应答和以RB依赖性方式呈递抗原相关的多个基因相关。使用单细胞测序和互补方法，我们发现CDK4/6和MEK抑制的组合对增加T细胞浸润和改变骨髓细胞群具有显著影响，同时与免疫检查点抑制剂有效合作。总之，这些数据表明，CDK4/6和MEK抑制存在影响肿瘤和免疫微环境的典型和非典型特征。这种组合靶向治疗可以与免疫检查点抑制剂治疗相结合，促进强大的肿瘤控制。
This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer. Patient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment. We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour progression. These effects were associated with stable cell-cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single-cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors. Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy.
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