Ontogeny and Function of Tumor-Resident Innate Lymphocytes and Innate-Like T Cells

肿瘤固有淋巴细胞和先天样 T 细胞的个体发育和功能

基本信息

批准号：
10415158
负责人：
Ming Li
金额：
$ 50.08万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415158
关键词：
Ablation Agonist Alleles Antigens CD8-Positive T-Lymphocytes CDH1 gene Cancer Patient Carcinoma Cell Differentiation process Cell Lineage Cell Maintenance Cells Cellular Immunity Characteristics Chromatin Development Diphtheria Toxin E-Cadherin Enterobacteria phage P1 Cre recombinase Exhibits Gene Expression Genetic Granzyme Growth Hematopoietic stem cells Hot Spot Immune response Immune system Immunologic Surveillance Immunotherapy Integrins Interleukin 2 Receptor Gamma Interleukin-15 Intestines Investigation Life Lymphocyte Lymphocyte Function Lymphoid Cell Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Missense Mutation Modality Mouse Strains Mus Names Natural Killer Cells Oncogenes Parabiosis Pathway interactions Patient Care Patients Process Receptor Signaling Regulation Renal Cell Carcinoma Reporter Residencies Role Sampling Sentinel Signal Transduction Solid Neoplasm Specific qualifier value T cell differentiation T cell response T-Cell Receptor T-Lymphocyte Testing Thymus Gland Tissue Expansion Tissues Transforming Growth Factor beta Transgenic Mice Tumor Escape Tumor Tissue adherent junction alpha Toxin autoreactive T cell base cancer cell cancer immunotherapy cancer therapy cancer type cell transformation cytokine cytotoxic cytotoxicity exhaust experimental study gain of function genomic locus immune checkpoint blockade insight intraepithelial intravital imaging mouse model neoplastic cell novel perforin programs receptor response stem cells targeted treatment transcription factor transcriptome tumor tumor growth tumor progression

项目摘要

Project Summary Cancer immunosurveillance ascribes a role of the immune system in repressing tumor development. Cancer immunotherapy approaches such as checkpoint blockade that revives this function of exhausted T cells have revolutionized cancer patient care. Nonetheless, many patients do not respond to this modality of cancer treatment, calling for investigation of a broader spectrum of tumor-elicited immune responses. We have recently shown that tumor growth induces expansion of tissue-resident cytotoxic innate lymphocytes and innate-like T cells that share a gene expression program distinct from that of NK cells and exhausted T cells. Characterized by high expression of the transcription factor Hobit and cytolytic granzymes, these cells are herein named killer innate lymphoid cells (ILCk) and killer innate-like T cells (ILTCk). Notably, genetic depletion of ILCk and ILTCk results in accelerated tumor growth. Furthermore, tumor cells express high levels of IL-15 and lose E-cadherin polarity, and IL-15 or E-cadherin deficiency depletes ILCk and ILTCk resulting in accelerated tumor growth. Based on these findings, we hypothesize that ILCk and ILTCk are novel lineages of cytotoxic lymphocytes, and they function as sentinels of cell transformation by sensing tumor cell-derived IL-15 and E-cadherin. To test this hypothesis, we will first define the developmental pathways of ILCk and ILTCk. By performing cell transfer and cell fate-mapping experiments as well as using mice deficient in lineage-specifying transcription factors, we will assess whether ILCk are differentiated along the innate lymphoid cell lineage. In addition, we will generate T cell receptor (TCR) retrogenic mice and perform TCR “swapping” experiments to determine whether distinct thymic selection promotes ILTCk differentiation. Parabiosis and inducible hematopoietic stem cell-targeted cell fate-mapping experiments will also be performed to determine whether ILCk and ILTCk are continuously generated throughout tumor progression. Secondly, we will define the function and regulation of ILCk and ILTCk by initially assessing whether Hobit expression marks a stage of functional specification, and whether Hobit controls a gene expression program essential for ILCk and ILTCk- mediated cancer surveillance. In addition, we will utilize conditional null alleles of Il15 and Il2rb and a gain-of- function allele encoding an active form of the transcription factor Stat5b to determine whether tumor IL-15 functions as an alarmin for ILCk and ILTCk, and whether IL-15 signaling constitutes a rate-limiting step of the ILCk and ILTCk response. Finally, we will investigate the interactions between tumor cells and ILCk and ILTCk by intravital imaging, and assess whether E-cadherin is sensed by the TGF-b-induced integrin CD103, and whether patient CDH1 hot-spot missense mutations promote tumor evasion from ILCk and ILTCk-mediated cancer surveillance. Successful completion of this project will not only generate mechanistic insights into the lineage commitment and regulation of tumor-resident ILCk and ILTCk, but also guide the targeting of this novel cancer immunosurveillance pathway for therapy of a wide range of malignancies.

项目概要癌症免疫监视归因于免疫系统在抑制肿瘤发展中的作用。诸如检查点封锁之类的免疫治疗方法可以恢复耗尽的 T 细胞的这种功能然而，许多患者对这种癌症治疗方式没有反应。治疗，呼吁研究更广泛的肿瘤引起的免疫反应。最近表明，肿瘤生长会诱导组织驻留细胞毒性先天淋巴细胞的扩张，先天性 T 细胞，具有与 NK 细胞和耗竭 T 细胞不同的基因表达程序。这些细胞的特点是转录因子 Hobit 和溶细胞颗粒酶的高表达，本文将其命名为先天杀伤性淋巴细胞 (ILCk) 和先天杀伤性 T 细胞 (ILTCk)。 ILCk 和 ILTCk 的结合导致肿瘤生长加速，此外，肿瘤细胞表达高水平的 IL-15。并失去 E-钙粘蛋白极性，IL-15 或 E-钙粘蛋白缺乏会耗尽 ILCk 和 ILTCk，导致基于这些发现，我们发现 ILCk 和 ILTCk 是新的谱系。细胞毒性淋巴细胞，它们通过感知肿瘤细胞衍生的 IL-15 作为细胞转化的哨兵为了验证这一假设，我们首先定义 ILCk 和 ILTCk 的发育途径。进行细胞转移和细胞命运图谱实验以及使用谱系特异性缺陷的小鼠转录因子，我们将评估 ILCk 是否沿先天淋巴细胞谱系分化。此外，我们将培育T细胞受体（TCR）逆转录小鼠并进行TCR“交换”实验确定不同的胸腺选择是否促进 ILTCk 联体共生和诱导型分化。还将进行造血干细胞靶向细胞命运图谱实验以确定是否 ILCk 和 ILTCk 在肿瘤进展过程中不断产生。通过初步评估 Hobit 表达是否标志着 ILCk 和 ILTCk 的一个阶段来了解 ILCk 和 ILTCk 的功能和调节功能规范，以及 Hobit 是否控制 ILCk 和 ILTCk 所必需的基因表达程序- 此外，我们将利用 Il15 和 Il2rb 的条件无效等位基因以及增益 - 编码转录因子 Stat5b 活性形式的功能等位基因可确定肿瘤 IL-15 是否存在作为ILCk和ILTCk的警报器，以及IL-15信号是否构成ILCk和ILTCk的限速步骤 ILCk 和 ILTCk 反应最后，我们将研究肿瘤细胞与 ILCk 和 ILTCk 之间的相互作用。通过活体成像，评估 E-钙粘蛋白是否被 TGF-b 诱导的整合素 CD103 感知，以及患者CDH1热点错义突变是否促进肿瘤逃避ILCk和ILTCk介导的癌症监测的成功完成不仅将产生对癌症监测的机制见解。肿瘤驻留 ILCk 和 ILTCk 的谱系定型和调节，也指导了该新药的靶向用于治疗多种恶性肿瘤的癌症免疫监视途径。