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时间， 横跨多种癌症类型。值得注意的是，免疫疗法可能是治愈的，然而，只有一小部分癌症患者- 轮胎对ICIS有强烈的持久反应。不同癌症类型的应答率也有很大差异， 一些ICIS只对少数癌症有效。造成这种情况的原因尚不清楚，强调 进一步研究的必要性。 许多ICIS，如针对PD-1/PD-L1途径的抗体，作用于肿瘤特异性T细胞 在病人被诊断出患有癌症的时候与癌症作斗争。这些疗法使T细胞恢复活力，并 导致它们攻击癌症，有时还会摧毁癌症。对T细胞介导的热休克反应知之甚少。 治疗反应或影响其治疗效果的因素。因此，人们对威慑- 挖掘这些疗法是如何起作用的，并对其进行强化，从而提高应答率。不幸的是，它 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，并导致癌症的发生。 可保护的抗肿瘤免疫反应。基因工程小鼠(GEM)模型被广泛用于种系研究。 IES在癌症生物学领域，因为它们允许研究人员研究发展中的肿瘤，并了解如何治疗癌症。 MORS在病程中会发生变化。然而，这些黄金标准模型并未用于癌症免疫学。 研究是因为肿瘤不表达新抗原，而新抗原是抗肿瘤T细胞反应所必需的。 发展肿瘤表达新抗原的GEM模型一直是具有挑战性的。为了解决这个问题， 我们设计了“忍者”小鼠，在这个计划中，我们将使用忍者来产生“免疫原性”宝石。 癌症模型(即引起抗癌免疫反应的模型)。我们将规范免疫原性 在肺癌和胰腺癌模型中，研究新抗原如何改变免疫细胞对肿瘤细胞的渗透。 MORS，并证实它们的翻译潜力是对人类癌症的忠实模仿。此外，我们还将发展 来自这些免疫原性宝石的细胞系和器官模型，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能够在早期(之前)观察肺和胰腺肿瘤 癌症的诊断)，并弄清楚这些早期肿瘤和免疫细胞是如何相互作用的。 此外，我们的研究将验证忍者作为一个平台，可以被其他研究人员用于属- 为其他癌症类型提供免疫原性宝石。由于这些模型可以用来改善PA的响应，因此，这些模型可以用来改善PAS的响应。 对于免疫疗法，忍者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.