Developing translationally-relevant genetically engineered mouse models of lung adenocarcinoma for investigations in cancer immunology

免疫检查点抑制剂（ICIs）正在延长晚期转移性癌症患者的生存期， 跨越多种癌症类型。值得注意的是，免疫疗法可能具有治愈性，但只有一小部分癌症能够治愈。 消费者对 ICI 有强烈持久的反应。癌症类型之间的反应率也有很大差异，并且 一些 ICI 仅对少数癌症有效。造成这种情况的原因尚不清楚，强调 需要进一步研究。 许多 ICI，如针对 PD-1/PD-L1 通路的抗体，作用于已经存在的肿瘤特异性 T 细胞。 在患者被诊断出患有疾病时对抗癌症。这些疗法可以重振 T 细胞并 使它们攻击甚至有时摧毁癌症。对于介导治疗的 T 细胞知之甚少 自然反应或调节其治疗效果的因素。因此，人们对阻止 挖掘这些疗法的作用并增强它们，从而提高反应率。不幸的是，它 这并不容易，因为很少有动物模型能够重现人类癌症的自然生物学并引起人们的注意。 可检测的抗肿瘤免疫反应。基因工程小鼠（GEM）模型广泛用于研究 癌症生物学领域的研究，因为它们使研究人员能够研究正在发展的肿瘤并了解如何进行治疗 mors随病程而变化。然而，这些金标准模型并不用于癌症免疫学 研究发现，肿瘤不表达新抗原，而新抗原是抗肿瘤 T 细胞反应所必需的。 开发肿瘤表达新抗原的 GEM 模型一直具有挑战性。为了解决这个问题， 我们设计了“NINJA”小鼠，在本提案中，我们将使用 NINJA 来生成“免疫原性”GEM 癌症模型（即引发抗癌免疫反应的模型）。我们将标准化免疫原性 肺癌和胰腺癌模型，研究新抗原如何改变免疫细胞浸润到肿瘤细胞 mors，并确认它们作为人类癌症的忠实模仿者的转化潜力。此外，我们还将开发 来自这些免疫原性 GEM 的细胞系和类器官模型，这将大大增加可用的工具 肺癌和胰腺癌研究人员。 这些最先进的模型将使科学家能够在早期阶段（在出现之前）观察肺和胰腺肿瘤。 癌症将在患者身上被诊断出来），并弄清楚这些早期肿瘤和免疫细胞如何相互作用。 此外，我们的研究将验证 NINJA 作为一个平台，可供其他研究人员用于一般研究。 用于其他癌症类型的免疫原性 GEM 的重刑。由于这些模型可用于改善pa- 对于免疫疗法，NINJA 将有助于增强几乎所有 GEM 模型的适用性 转化研究。

Immune checkpoint inhibitors (ICIs) are extending the survival of patients with advanced, metastatic cancer, across many cancer types. Remarkably, immunotherapies may be curative, yet, only a fraction of cancer pa- tients have strong durable responses to ICIs. Response rates also differ greatly between cancer types, and some ICIs are only effective against a handful of cancers. The reasons for this remain unclear, underscoring the need for further research. Many ICIs, like antibodies targeting the PD-1/PD-L1 pathway, act on tumor-specific T cells that are already fighting the cancer at the time the patient is diagnosed with disease. The therapies reinvigorate T cells and cause them to attack and sometimes destroy the cancer. Little is known about the T cells that mediate thera- peutic responses or the factors that modulate their therapeutic efficacy. Thus, there is great interest in deter- mining how these therapies work and in augmenting them so that response rates increase. Unfortunately, it has not been easy, because few animal models recapitulate the natural biology of human cancer and elicit de- tectable anti-tumor immune responses. Genetically engineered mouse (GEM) models are widely used for stud- ies in cancer biology because they allow investigators to study developing tumors and to understand how tu- mors change over the course of disease. Yet, these gold-standard models are not used for cancer immunology studies because tumors do not express neoantigens, which are required for anti-tumor T cell responses. It has been challenging to develop GEM models where tumors express neoantigens. To remedy this problem, we engineered the “NINJA” mouse, and, in this proposal, we will use NINJA to generate “immunogenic” GEM models for cancer (i.e., models that elicit anti-cancer immune responses). We will standardize immunogenic models for lung and pancreatic cancer, investigate how neoantigens alter the immune cell infiltrates into tu- mors, and confirm their translational potential as faithful mimics of human cancer. Moreover, we will develop cell line and organoid models from these immunogenic GEMs, which will greatly increase the available tools for researchers in lung and pancreatic cancer. These state-of-the-art models will allow scientists to look at lung and pancreatic tumors at early stages (before cancers would be diagnosed in a patient), and to figure out how these early tumors and immune cells interact. Moreover, our studies will validate NINJA as a platform that can be used by other investigators for the genera- tion of immunogenic GEMs for other cancer types. As these models can be used to improve responses of pa- tients to immunotherapy, NINJA will be useful for enhancing the applicability of almost any GEM model for translational research.