An Immunogenic Model of KRAS-Mutant Lung Cancer Enables Evaluation of Targeted Therapy and Immunotherapy Combinations.

Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumor mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, anti-tumor immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C-expressing tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.

诸如KRAS和EGFR等癌基因的突变导致了很大比例的肺癌。针对这些蛋白质的药物可使肿瘤消退，但最终无法实现治愈。因此，人们对如何将靶向疗法与其他治疗方法（如免疫疗法）最佳结合产生了浓厚兴趣。然而，用于研究肺肿瘤与宿主免疫系统相互作用的临床前系统并不完善，部分原因是基因工程小鼠模型中的肿瘤突变负荷较低。在此，我们着手通过表达人类DNA胞嘧啶脱氨酶APOBEC3B来开发具有较高肿瘤突变负荷的突变KRAS驱动的肺癌小鼠模型，以模拟人类肺癌中所见的突变特征。这未能大幅增加克隆性肿瘤突变负荷，原位肿瘤对免疫疗法仍然具有抗性。然而，从这些肿瘤建立克隆细胞系使得能够生成对免疫疗法敏感的KRAS突变肺腺癌的免疫原性同基因移植模型。出乎意料的是，抗肿瘤免疫反应并非针对新抗原，而是针对去抑制的内源性逆转录病毒抗原。适应性免疫系统显著增强了KRASG12C抑制剂使表达KRASG12C的肿瘤消退的能力，突显了使用免疫健全模型评估靶向疗法的重要性。总体而言，该模型为研究免疫热肺癌中靶向疗法和免疫疗法的组合提供了独特的机会。