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

免疫检查点抑制剂（ICI）正在延长晚期转移性癌症患者的生存期， 在许多癌症类型中。值得注意的是，免疫疗法可能是治愈性的，然而，只有一小部分癌症患者， 患者对ICI有较强的持久反应。癌症类型之间的反应率也有很大差异， 一些ICI仅对少数癌症有效。其原因尚不清楚，强调 需要进一步研究。 许多ICI，如靶向PD-1/PD-L1通路的抗体，作用于已经免疫的肿瘤特异性T细胞。 在病人被诊断出患有癌症时与癌症作斗争。这些疗法可以重振T细胞， 导致它们攻击并有时摧毁癌症。对介导治疗的T细胞知之甚少， 或调节其疗效的因素。因此，有很大的兴趣，在制止- 挖掘这些疗法的工作原理并增强它们，以便提高响应率。可惜 这并不容易，因为很少有动物模型能概括人类癌症的自然生物学，并引起疾病的发生。 可检测的抗肿瘤免疫应答。基因工程小鼠（GEM）模型广泛用于研究， 癌症生物学的研究，因为它们使研究人员能够研究发展中的肿瘤，并了解肿瘤是如何发生的， MORS在疾病过程中发生变化。然而，这些黄金标准模型并不用于癌症免疫学 因为肿瘤不表达抗肿瘤T细胞应答所需的新抗原。 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产生“免疫原性”GEM 癌症模型（即，引发抗癌免疫应答的模型）。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中， MORS，并确认其作为人类癌症的忠实模拟物的翻译潜力。此外，我们将开发 细胞系和类器官模型，这将大大增加可用的工具， 肺癌和胰腺癌的研究人员。 这些最先进的模型将使科学家们能够在早期阶段（之前）观察肺和胰腺肿瘤。 癌症将在患者中被诊断出来），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，可用于其他研究人员的属- 免疫原性GEM对其他癌症类型的作用。由于这些模型可以用来改善响应的pa- 对于免疫治疗，NINJA将有助于增强几乎任何GEM模型的适用性， 翻译研究

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.