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.

项目摘要癌症免疫监测在表达肿瘤发育中分配了免疫系统的作用。癌症免疫疗法的方法，例如恢复这种耗尽T细胞功能的检查点阻滞具有革命性的癌症患者护理。但是，许多患者对癌症的这种方式没有反应治疗，要求投资更广泛的肿瘤引起的免疫反应。我们有最近表明，肿瘤的生长诱导组织居住的细胞毒性先天淋巴细胞和具有与NK细胞和耗尽T细胞的基因表达程序的先天性T细胞不同。这些细胞以转录因子和细胞溶剂粒的高表达为特征，这些细胞是此处命名为杀手型先天淋巴样细胞（ILCK）和杀手型先天的T细胞（ILTCK）。值得注意的是，遗传部署 ILCK和ILTCK导致肿瘤的加速生长。此外，肿瘤细胞表达高水平的IL-15 并失去电子钙粘蛋白极性，IL-15或E-钙粘着蛋白缺乏症耗尽ILCK和ILTCK，导致加速肿瘤生长。基于这些发现，我们假设ILCK和ILTCK是细胞毒性淋巴细胞，它们通过传感肿瘤细胞衍生的IL-15来充当细胞转化的哨兵和电子辅助蛋白。为了检验这一假设，我们将首先定义ILCK和ILTCK的发育途径。经过进行细胞转移和细胞命运图实验，以及使用缺乏谱系特异性的小鼠转录因子，我们将评估ILCK是否沿先天淋巴样细胞谱系分化。在此外，我们将生成T细胞受体（TCR）后源性小鼠，并执行TCR“交换”实验确定不同的胸腺选择是否促进了ILTCK分化。核核病和诱导还将进行造血干细胞细胞的细胞脂肪图实验，以确定是否是否在整个肿瘤进展过程中，ILCK和ILTCK都是连续产生的。其次，我们将定义通过最初评估Hobit表达是否标志着ILCK和ILTCK的功能和调节功能规范以及霍比特是否控制着ILCK和ILTCK-必不可少的基因表达程序介导的癌症监测。此外，我们将利用IL15和IL2RB的条件无效等位基因，以及 - 功能等位基因编码转录因子STAT5B的活动形式，以确定肿瘤IL-15是否是否充当ILCK和ILTCK的警报，以及IL-15信号是否构成限速步骤 ILCK和ILTCK响应。最后，我们将研究肿瘤细胞与ILCK和ILTCK之间的相互作用通过插入成像，并评估是否通过TGF-B诱导的整合素CD103感应E-钙粘蛋白，并且患者CDH1热点错义突变是否促进ILCK和ILTCK介导的肿瘤演变癌症监测。成功完成该项目不仅会产生机械洞察力肿瘤居民ILCK和ILTCK的谱系承诺和调节，但也指导了这项小说的靶向癌症免疫监视途径，用于治疗多种恶性肿瘤。