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II：原发结肠癌、淋巴结和肝脏的免疫调节回路 转移瘤 实验领队：鲁登斯基 计算主管：莱斯利 实验联合负责人：加内什 项目总结 结直肠癌(CRC)是美国和世界范围内第三大常见癌症。尽管有重大的 免疫疗法、错配修复熟练(PMMR)、结直肠癌治疗某些癌症的研究进展 占绝大多数(85%)的病例无反应，5年生存率约为15%。我们 假设这一故障是由于CRC促进免疫和间质局部回路的活动所致 辅助细胞，其中抑制性调节性T(Treg)细胞和非炎性组织支持性Th17 细胞是必不可少的组成部分。我们还提出，这些T细胞的结构和细胞组成 细胞环路在原发结直肠癌、近端淋巴结和远端肝转移瘤中有明显区别。在这个项目中， 我们将解剖包括Treg和Th17细胞在内的主要免疫调节细胞状态的动态以及它们的 原发肿瘤和淋巴结中细胞成分(“免疫调节邻域”)的相互作用 在同一组pMMR结直肠癌患者中发生肝转移，同时建立了一种新的自发小鼠遗传模型 转移性pMMR CRC(目标1)。我们的扰动研究将阐明这些关键的免疫调节作用 细胞及其伙伴在转移性疾病进展和免疫治疗抵抗中的作用(目标2)和检查 关键免疫细胞衍生因子对人原发和转移性结直肠癌有机物中癌细胞的影响 (目标3)。我们将在单个单元格分辨率下结合空间分析使用尖端的“组学”分析 转录学和高度多元化的光学成像与显微镜和流式细胞术相结合 用新的解构原型的计算建模和分析迭代实验扰动 结直肠癌中基于T细胞的细胞回路及其细胞染色质的保守状态和基因调控程序 选民。这些研究将有助于从机制上更好地理解前转移细胞的出现。 国家在pMMR结直肠癌和通知开发的正交合理的联合免疫疗法为此 并阐明靶向免疫上皮细胞通路预防和治疗的可行性。 治疗晚期结直肠癌患者的转移。 。