Group 2 Innate Lymphoid Cell Regulation of Pancreatic Cancer Immunity

项目摘要/摘要 增强抗肿瘤T细胞的免疫疗法是肿瘤学的里程碑式突破。然而，目前 免疫疗法直接激活T细胞，因此在T细胞很少的肿瘤中约80%无效。 肿瘤)。因此，肿瘤学中的一个主要挑战是为寒冷的肿瘤开发有效的免疫疗法。 胰腺导管腺癌(PDAC)就是一个很好的例子--~91%的肿瘤T细胞很少，因此 PDAC对目前的免疫疗法很少有反应(应答率为2%)。然而，免疫疗法是最重要的 在PDAC中有希望的选择，因为所有其他治疗都失败了，只有罕见的(9%)免疫原性患者 “热”瘤(瘤内高密度T细胞)可以长期存活。因此，迫切需要新的免疫疗法。 该原理也可应用于其他冷肿瘤。 为了发现在PDAC中主动免疫的新靶点，我们对比了罕见的长肿瘤中的免疫细胞。 长期PDAC存活者从短期存活者转变为更典型的冷瘤患者。没想到，我们发现 热性肿瘤的第二组固有淋巴样细胞(ILC2s)密度高出约3倍(Moral等人，《自然》，2020)。 ILC2是一种淋巴细胞，可以在感染时放大CD4+Th2细胞，但矛盾的是，它可以激活CD8+T细胞 肿瘤。在小鼠模型中，我们发现ILC2招募CD103+树突状细胞来激活CD8+T细胞，并 抑制主PDAC。通过进一步的研究，我们现在发现，与目前推测的不同，ILC2 也可以迁移以抑制转移的PDAC肿瘤，表达淋巴毒素(LT)，这是一种诱导第三代 肿瘤中的淋巴结构，并表达调节其抗肿瘤功能的免疫检查点PD-1。 因为我们是第一个报告ILC2可以激活PDAC免疫的小组，ILC2通过什么机制 抑制PDAC，从而为合理的策略提供信息，以便在免疫治疗中利用它们，目前尚不清楚。 因此，我们现在建议研究ILC2如何迁移到肿瘤，激活CD8+T细胞，并在功能上 受监管的。通过对人类PDAC患者ILC2表型和功能的综合、多学科研究， 患者衍生的有机化合物，以及在小鼠模型中的功能研究，我们将：1)定义动员 抗肿瘤ILC2s；2)研究抗肿瘤ILC2s如何利用LT激活CD8+T细胞；3)展示 PD-1阻断如何增强抗肿瘤ILC2功能。为了确保采用跨学科的方法，我们将使用 经验丰富的调查团队，在PDAC生物学、ILC2免疫学、 免疫疗法、器官模型和计算肿瘤学。我们希望我们的建议能为 了解ILC2癌症生物学的框架，并指导在新的免疫疗法中利用ILC2的努力。

PROJECT SUMMARY/ABSTRACT Immunotherapies that boost anti-tumor T cells are landmark breakthroughs in oncology. Yet, current immunotherapies directly activate T cells and are therefore ineffective in ~80% of tumors with few T cells (“cold” tumors). Thus, a primary challenge in oncology is to develop effective immunotherapies for cold tumors. Pancreatic ductal adenocarcinoma (PDAC) is a prime example – ~91% of tumors have few T cells, and thus PDAC rarely responds to current immunotherapies (<2% response rate). Yet, immunotherapy is the most promising option in PDAC, as all other therapies have failed, and only the rare (9%) patients with immunogenic “hot” tumors (high density of intratumoral T cells) survive long-term. Thus, new immunotherapies are urgently needed for PDAC, and the principles can be applied to other cold tumors. To discover new targets that active immunity in PDAC, we contrasted immune cells in hot tumors from rare long- term PDAC survivors to those in more typical cold tumors from short-term survivors. Unexpectedly, we found that hot tumors have ~3-fold higher densities of group 2 innate lymphoid cells (ILC2s) (Moral et al., Nature, 2020). ILC2s are lymphocytes that amplify CD4+ Th2 cells in infection but paradoxically can activate CD8+ T cells in tumors. Using mouse models, we found that ILC2s recruit CD103+ dendritic cells to activate CD8+ T cells and suppress primary PDACs. Through further studies, we have now found that unlike currently presumed, ILC2s can also migrate to suppress metastatic PDAC tumors, express lymphotoxin (LT), a protein that induces tertiary lymphoid structures in tumors, and express the immune checkpoint PD-1 that regulates their anti-tumor function. As we are the first group to report that ILC2s can activate immunity in PDAC, the mechanisms by which ILC2s suppress PDACs, which can thus inform rational strategies to harness them in immunotherapies, are unknown. Thus, we now propose to study how ILC2s migrate to tumors, activate CD8+ T cells, and are functionally regulated. Through integrated, multi-disciplinary study of ILC2 phenotype and function in human PDAC patients, patient-derived organoids, and functional studies in mouse models, we will: 1) define the cytokines that mobilize anti-tumor ILC2s; 2) investigate how anti-tumor ILC2s utilize LT to activate CD8+ T cells; and 3) demonstrate how PD-1 blockade enhances anti-tumor ILC2 function. To ensure a cross-disciplinary approach, we will use an experienced team of investigators with complementary skills in PDAC biology, ILC2 immunology, immunotherapy, organoid models, and computational oncology. We expect our proposal will lay the scientific framework to understand ILC2 cancer biology and guide efforts to harness ILC2s in new immunotherapies.