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

• 批准号: 10705782
• 负责人: Alexander Y Rudensky
• 金额: $ 73.46万
• 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: 2022-09-16 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705782
• 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; Epithelium; 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; Mismatch Repair Deficiency; Modality; Mus; Mutagenesis; Neighborhoods; Neoplasm Metastasis; Organoids; Patients; 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; 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; multiple omics; neoplastic cell; novel; optical imaging; pharmacologic; prevent; programs; receptor; stem cells; tool; transcriptome sequencing; transcriptomics; tumor; tumor progression

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. .

项目二。原发性结肠癌、淋巴结和肝脏中的免疫调节回路 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。尽管主要 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%) 病例的患者未能得到缓解，5 年生存率约为 15%。我们 假设这种失败是由于促进 CRC 的免疫和基质局部回路的活性所致 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 细胞是重要的组成部分。我们还提出这些 T 的结构和细胞组成 原发性 CRC 以及近端淋巴结和远端肝转移的细胞回路是不同的。在这个项目中， 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 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）。我们将采用尖端的“组学”分析，以单细胞分辨率结合空间分析 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 选民。这些研究将使人们更好地理解促转移细胞出现的机制 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。 。