Harnessing CDK4/6 inhibition to promote T cell-mediated anti-tumor immunity

癌症是全球主要的死亡原因，预计其数量将进一步上升，2030年估计将导致1200万人死亡。在这些与癌症相关的死亡中，有很大一部分可归因于肺癌。尽管针对肺腺癌的靶向治疗(约40%的肺癌)已经发展起来(如Erlotinib、Alectinib)，侵袭性的、非激酶KRAS驱动的肺腺癌直到今天仍然难以有针对性的治疗策略。此外，KRAS突变经常与关键抑癌基因的同时丢失有关，例如这种肿瘤类型中的TP53或STK11/LKB1。目前，当免疫检查点抑制剂治疗肺癌时，观察到提高了应答率，从而唤起了患者自身的适应性抗肿瘤免疫。然而，目前只有一小部分患者有反应，很可能需要应用多模式治疗来治疗KRAS驱动的肺腺癌。本研究的总体目标是探讨放射治疗(RTX)和CDK4/6抑制剂是否协同作用，使Kras驱动的肺腺癌对免疫检查点抑制物(ICIS)增敏。具体地说，我们的目标是确定抑制CDK4/6在体外对效应性T细胞的影响。其次，我们将分析体内肿瘤免疫微环境对CDK4/6的抑制作用。了解CDK4/6抑制后免疫细胞群和功能的改变将有助于我们选择添加其他抗癌化合物的时机。最后，我们将进行一项临床前研究，以评估二联疗法(CDK4/6抑制+RTX)或三联疗法(CDK4/6抑制+RTX+免疫检查点抑制剂)对Kras驱动的肺腺癌是否具有协同抗肿瘤效果。最终，该项目的发现将帮助临床医生设计针对患者的知情定制临床研究，以便在人类环境中进行快速翻译。

Cancer is the leading cause of death worldwide and its numbers are projected to rise further, resulting in an estimated 12 million deaths in 2030. A significant amount of these cancer-related deaths is attributable to lung cancer. Although targeted therapies for lung adenocarcinomas (approx. 40% of all lung cancers) have been developed (e.g. Erlotinib, Alectinib), aggressive, non-kinase KRAS-driven lung adenocarcinoma remains refractory to targeted treatment strategies until today. Additionally, KRAS mutations are frequently associated with concurrent loss of key tumor suppressor genes, such as TP53 or STK11/LKB1 in this tumor type. Currently, increased response rates of lung cancers are observed when treated with immune checkpoint inhibitors rearousing the patient´s own adaptive anti-tumor immunity. However, only a minority of patients responds yet, and it is highly likely that application of multimodal therapy is required to tackle KRAS-driven lung adenocarcinoma. The overall aim of this study addresses the question whether radiation therapy (RTx) and CDK4/6 inhibitors act synergistically to sensitize Kras-driven lung adenocarcinoma towards immune checkpoint inhibitors (ICIs). Specifically, we aim to define the effects of CDK4/6 inhibition on effector T cells in vitro. Secondly, we will analyse the tumor immune microenvironment upon CDK4/6 inhibition in vivo. Knowledge of altered immune cell populations and functions upon CDK4/6 repression will help us in timing the addition of other anti-cancer compounds. Lastly, we will perform a preclinical study to evaluate whether dual modality therapy (CDK4/6 inhibition + RTx), or triple modality therapy (CDK4/6 inhibition + RTx + immune check point inhibitor) have synergistic anti-tumor efficacy towards Kras-driven lung adenocarcinoma. Ultimately, the findings from this project will help clinicians to design informed patient-tailored clinical studies for rapid translation in the human setting.