Group 2 Innate Lymphoid Cell Regulation of Pancreatic Cancer Immunity

第 2 组先天淋巴细胞对胰腺癌免疫的调节

• 批准号: 10446222
• 负责人: Vinod P Balachandran
• 金额: $ 62.31万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446222
• 关键词: Active immunity; Biology; CD8-Positive T-Lymphocytes; Cancer Biology; Cell physiology; Cells; Cellular biology; Clinical Trials; Data; Dendritic Cells; Engineering; Ensure; Future; Goals; Human; Immune; Immunity; Immunology; Immunooncology; Immunotherapy; Infection; Interleukins; Ligands; Lymphocyte; Lymphoid Cell; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Molecular; Molecular Genetics; Morals; Mus; Nature; Neoplasm Metastasis; Oncology; Organoids; PD-1 blockade; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Proteins; Regulation; Reporting; Research Personnel; Sampling; Survivors; T-Lymphocyte; Testing; Th2 Cells; Tissues; Transgenic Organisms; Tumor Immunity; Tumor Necrosis Factor-Beta; chemokine; cytokine; density; experience; immune checkpoint; immunogenic; mouse model; multidisciplinary; novel; programmed cell death protein 1; rare cancer; recruit; response; skills; stem cells; tertiary lymphoid organ; therapeutic target; tool; transcriptomics; translational potential; tumor

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.

项目总结/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，因此在约80%的T细胞较少的肿瘤中无效（“冷”）。 肿瘤）。因此，肿瘤学的主要挑战是为冷肿瘤开发有效的免疫疗法。 胰腺导管腺癌（PDAC）是一个很好的例子-约91%的肿瘤几乎没有T细胞，因此 PDAC很少对目前的免疫疗法有反应（<2%的反应率）。然而，免疫疗法是最 这是PDAC中有希望的选择，因为所有其他疗法都失败了，只有极少数（9%）免疫原性 “热”肿瘤（高密度的肿瘤内T细胞）长期存活。因此，新的免疫疗法迫切需要 PDAC所需的，原则可以应用于其他冷肿瘤。 为了发现在PDAC中激活免疫的新靶点，我们将热肿瘤中的免疫细胞与罕见的长- 从短期存活者到更典型的冷肿瘤中的PDAC存活者。出乎意料的是，我们发现 热肿瘤具有约3倍高密度的第2组先天淋巴样细胞（ILC 2）（Moral等人，Nature，2020）。 ILC 2是淋巴细胞，在感染中扩增CD 4 + Th 2细胞，但矛盾的是，在感染中可以激活CD 8 + T细胞。 肿瘤的使用小鼠模型，我们发现ILC 2招募CD 103+树突状细胞来激活CD 8 + T细胞， 抑制主要PDAC。通过进一步的研究，我们现在发现，与目前推测的不同，ILC 2 也可以迁移以抑制转移性PDAC肿瘤，表达光敏素（LT），一种诱导三级细胞凋亡的蛋白质， 在肿瘤中的淋巴结构，并表达调节其抗肿瘤功能的免疫检查点PD-1。 由于我们是第一组报道ILC 2可以激活PDAC中的免疫，ILC 2激活PDAC的机制是： 因此，抑制PDAC可以为在免疫治疗中利用它们合理策略提供信息。 因此，我们现在建议研究ILC 2如何迁移到肿瘤，激活CD 8 + T细胞，并在功能上与肿瘤细胞结合。 监管.通过对人类PDAC患者中ILC 2表型和功能的综合、多学科研究， 患者来源的类器官，以及小鼠模型中的功能研究，我们将：1）定义动员的细胞因子 抗肿瘤ILC 2; 2）研究抗肿瘤ILC 2如何利用LT来活化CD 8 + T细胞;和3）证明 PD-1阻断如何增强抗肿瘤ILC 2功能。为了确保跨学科的方法，我们将使用 经验丰富的研究团队，在PDAC生物学，ILC 2免疫学， 免疫疗法、类器官模型和计算肿瘤学。我们希望我们的提议能为科学 该框架旨在了解ILC 2癌症生物学，并指导在新的免疫疗法中利用ILC 2的努力。