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: 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
• 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

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。原发性结肠癌和淋巴结和肝脏中的免疫调节回路 转移 实验铅：鲁登斯基 计算负责人：莱斯利 实验共同领导：Ganesh 项目摘要 大肠癌（CRC）代表了美国和全球第三大常见的癌症。尽管很重要 免疫疗法，不匹配维修（PMMR）CRC的某些癌症的治疗进展， 这占绝大多数案件（85％）的情况，未能以约15％的5年生存率做出回应。我们 假设这种故障是由于免疫和基质的促进CRC局部电路的活性 辅助细胞，其中抑制性调节T（Treg）细胞和非炎性组织支持TH17 细胞是必不可少的组成部分。我们还建议这些T的结构和细胞组成 细胞回路在原发性CRC和近端淋巴结和盘状肝转移中是不同的。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态的动力学及其 与原发性肿瘤和淋巴结中的细胞成分（“免疫调节社区”）相互作用 在同一PMMR CRC患者中的肝转移以及一种新型的赞助商友好的小鼠遗传模型 转移PMMR CRC（AIM 1）。我们的扰动研究将阐明这些关键免疫调节的作用 细胞及其在转移性疾病进展和对免疫疗法的抵抗力的伴侣（AIM 2）并检查 关键免疫细胞衍生因子对人原发性和转移性CRC器官中癌细胞的影响 （目标3）。我们将在单个细胞分辨率和空间的单元分析下采用最前沿的“ OMICS”分析 转录组学以及高度多路复用的光学成像和显微镜以及流式细胞术耦合到 实验性扰动迭代进行新的计算建模和分析以解构原型 CRC中基于T细胞的细胞电路和配置的染色质状态和其细胞的基因调节程序 成分。这些研究将使对促迁移细胞的紧急情况有更好的机械理解 PMMR CRC中的各州并为此提供了正交理性组合免疫疗法的开发 疾病并阐明靶向免疫上皮回路预防和 治疗晚期CRC患者的转移。 。