Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
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Cell Rep Methods. 2021 Sep 27;1(5). doi: 10.1016/j.crmeth.2021.100080. Epub 2021 Sep 16.
Kras-driven lung adenocarcinoma (LUAD) is the most common lung cancer. A significant fraction of patients with Kras-driven LUAD respond to immunotherapy, but mechanistic studies of immune responses against LUAD have been limited because of a lack of immunotherapy-responsive models. We report the development of the immunogenic KP × NINJA (inversion inducible joined neoantigen) (KP-NINJA) LUAD model. This model allows temporal uncoupling of antigen and tumor induction, which allows one to wait until after infection-induced inflammation has subsided to induce neoantigen expression by tumors. Neoantigen expression is restricted to EPCAM+ cells in the lung and expression of neoantigen was more consistent between tumors than when neoantigens were encoded on lentiviruses. Moreover, tumors were infiltrated by tumor-specific CD8 T cells. Finally, LUAD cell lines derived from KP-NINJA mice were immunogenic and responded to immune checkpoint therapy (anti-PD1 and anti-CTLA4), providing means for future studies into the immunobiology of therapeutic responses in LUAD.
Kras 驱动的肺腺癌 (LUAD) 是最常见的肺癌。相当一部分 Kras 驱动的 LUAD 患者对免疫疗法有反应，但由于缺乏免疫治疗反应模型，针对 LUAD 的免疫反应的机制研究一直受到限制。我们报告了免疫原性 KP × NINJA（反转诱导连接新抗原）（KP-NINJA）LUAD 模型的开发。该模型允许抗原和肿瘤诱导的时间解耦，这使得人们可以等到感染诱导的炎症消退后，再通过肿瘤诱导新抗原表达。新抗原仅在肺中的 EPCAM+细胞中表达，并且与将新抗原编码在慢病毒上相比，肿瘤之间的新抗原表达更为一致。此外，肿瘤被肿瘤特异性 CD8 T 细胞浸润。最后，源自 KP-NINJA 小鼠的 LUAD 细胞系具有免疫原性，并对免疫检查点治疗（抗 PD1 和抗 CTLA4）有反应，为未来研究 LUAD 治疗反应的免疫生物学提供了手段。
