Project II: Immune regulatory circuits in primary colon cancer and lymph node and liver metastases

项目二：原发性结肠癌及淋巴结和肝转移的免疫调节回路

基本信息

批准号：
10525193
负责人：
Alexander Y Rudensky
金额：
$ 78.77万
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：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525193
关键词：
ATAC-seq Ablation Acute Antibodies Antigen-Presenting Cells Architecture Biological Assay Carcinogens Cell Communication Cell Nucleus Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Colon Colon Carcinoma Colorectal Cancer Combination immunotherapy Combined Modality Therapy Computer Analysis Computer Models Coupled Cues Development Disease Disease Progression Disease Resistance Distal Epithelial Equilibrium Exposure to Failure Flow Cytometry Genetic Genetic Models Human Immune Immune Targeting Immune system Immunity Immunotherapy Inflammatory Inflammatory Response Intestines Lead Ligands Liver Maintenance Malignant Neoplasms Mediating Memorial Sloan-Kettering Cancer Center Metastatic Neoplasm to the Liver Microscopy Mismatch Repair Modality Mus Mutagenesis Neighborhoods Neoplasm Metastasis Organoids Patients Pharmacology Primary Neoplasm RNA Recombinants Regulator Genes Regulatory T-Lymphocyte Resolution Role Signal Pathway Site Stimulus Supporting Cell Survival Rate Systems Biology T cell receptor repertoire sequencing T-Lymphocyte Testing Therapeutic Tissues Transplantation antitumor effect base cancer cell carcinogenesis cell type checkpoint therapy chemokine colon cancer patients colorectal cancer progression combinatorial commensal microbes enteric infection experimental analysis immune checkpoint blockade immunoregulation lymph nodes lymphoid organ metastatic colorectal microbiota mouse genetics neoplastic cell novel optical imaging predictive test prevent programs receptor stem cells tool transcriptome sequencing transcriptomics tumor tumor progression

项目摘要

Project II. Immune regulatory circuits in primary colon cancer and lymph node and liver metastases Experimental Lead: Rudensky Computational Lead: Leslie Experimental Co-Lead: Ganesh PROJECT SUMMARY Colorectal cancer (CRC) represents the third most common cancer in the US and worldwide. Despite major advances in treatment of some cancer afforded by immunotherapy, mismatch repair-proficient (pMMR) CRC, which accounts for the vast majority (85%) of cases, fails to respond with ~15% 5-year survival rate. We hypothesize that this failure is due to the activity of CRC-promoting local circuits of immune and stromal accessory cells, in which suppressive regulatory T (Treg) cells and non-inflammatory tissue-supporting Th17 cells serve as essential components. We also propose that the architecture and cellular composition of these T cell circuits are distinct in primary CRC and in proximal lymph node and distal liver metastases. In this project, we will dissect the dynamics of the main immunomodulatory cells states including Treg and Th17 cell and their interactions with cellular components (“immunomodulatory neighborhoods”) in primary tumors and lymph node and liver metastases in the same pMMR CRC patients alongside a novel mouse genetic model of spontaneously metastasizing pMMR CRC (Aim 1). Our perturbation studies will elucidate roles of these key immunomodulatory cells and their partners in metastatic disease progression and resistance to immunotherapy (Aim 2) and examine the impact of key immune cell-derived factors on cancer cells in human primary and metastatic CRC organoids (Aim 3). We will employ cutting edge “omics” analyses at a single cell resolution combined with spatial transcriptomics and highly multiplexed optical imaging and microscopy and flow cytometry coupled to experimental perturbations iteratively with novel computational modeling and analyses to deconstruct archetypal T cell-based cell circuits in CRC and conserved chromatin states and gene regulatory programs of their cellular constituents. These studies will enable better mechanistic understanding of emergence of pro-metastatic cell states in pMMR CRC and inform development of orthogonal rational combination immunotherapies for this disease and elucidate the therapeutic actionability of targeting immune-epithelial circuits in preventing and treating metastasis in patients with advanced CRC. .

项目 II. 原发性结肠癌、淋巴结和肝脏的免疫调节回路转移实验负责人：Rudensky 计算主管：Leslie 实验联合负责人：Ganesh 项目概要结直肠癌 (CRC) 是美国和全世界第三大常见癌症。免疫疗法、错配修复良好 (pMMR) CRC 等某些癌症的治疗取得进展，占绝大多数 (85%) 病例的 5 年生存率约为 15%。研究认为，这种失败是由于 CRC 促进局部免疫和基质回路的活性所致。辅助细胞，其中抑制性调节性 T (Treg) 细胞和支持非炎症组织的 Th17 我们还提出这些 T 细胞的结构和细胞组成。细胞回路在原发性 CRC 以及近端淋巴结和远端肝转移中是不同的。我们将剖析包括 Treg 和 Th17 细胞在内的主要免疫调节细胞状态的动态及其与原发肿瘤和淋巴结中的细胞成分（“免疫调节邻域”）的相互作用和肝转移在相同的 pMMR CRC 患者中以及自发性的新型小鼠遗传模型转移性 pMMR CRC（目标 1）。我们的扰动研究将阐明这些关键免疫调节的作用。细胞及其伙伴在转移性疾病进展和免疫治疗耐药性（目标 2）中的作用并进行检查关键免疫细胞衍生因子对人类原发性和转移性结直肠癌类器官中癌细胞的影响（目标 3）我们将采用单细胞分辨率的尖端“组学”分析与空间分析相结合。转录组学和高度多重光学成像以及显微镜和流式细胞术耦合通过新颖的计算模型和分析迭代实验扰动来解构原型 CRC 中基于 T 细胞的细胞回路和保守染色质状态及其细胞的基因调控程序这些研究将有助于更好地理解促转移细胞的出现。 pMMR CRC 中的状态并为为此开发正交合理组合免疫疗法提供信息疾病并阐明靶向免疫上皮回路在预防和治疗中的治疗作用治疗晚期结直肠癌患者的转移。。