Investigating the Spatial Dynamics of Intratumoral Immune Cells in Breast Cancer

研究乳腺癌瘤内免疫细胞的空间动态

• 批准号: 10631936
• 负责人: Joseph Anthony Saglimbeni
• 金额: $ 5.27万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631936
• 关键词: Address; Affect; Antigen Presentation; Antitumor Response; Area; Bone Marrow; Breast Cancer Patient; Breast Cancer therapy; Cancer Etiology; Cell Communication; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Communication; Data; Dendritic Cells; Development; Dimensions; Disease; Disease Outcome; Disease Progression; Doxorubicin; Genetic; Goals; Hyperplasia; Imaging technology; Immune; Immunophenotyping; Immunosuppression; Immunotherapy; In Situ; Infiltration; Investigation; Leukocytes; Macrophage; Malignant Neoplasms; Mammary Neoplasms; Molecular; Mus; Neoplasm Metastasis; Paclitaxel; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Population; Positioning Attribute; Production; Regulatory T-Lymphocyte; Relapse; Role; T-Lymphocyte; Technology; Testing; Tissues; Tumor Antigens; Tumor Immunity; Tumor stage; Tumor-associated macrophages; Tumor-infiltrating immune cells; United States; Visualization; breast cancer progression; cancer cell; cancer type; cell type; cytokine; fetal; fluorescence imaging; high dimensionality; immune cell infiltrate; immunosuppressed; in situ imaging; interest; malignant breast neoplasm; mammary; mortality; mouse model; neoplastic cell; novel; organizational structure; pharmacologic; prognostic; response; spatiotemporal; standard of care; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

PROJECT ABSTRACT While immunotherapy has revolutionized the treatment of certain malignancies it has yet to yield the same results in breast cancer. This is striking, given that there is an abundance of intra-tumoral immune cells that affect disease outcomes. Evidence suggests that these leukocytes are strategically positioned to execute their functions and yet little is known about their spatial dynamics over tumor progression and regression. I aim to detail a comprehensive and mechanistic picture of these spatiotemporal dynamics using recent advances in high-dimensional in situ imaging. I hypothesize that as tumors progress, immunosuppressive cells will block immune cell organizational structures and cell-cell communications that promote antitumor immunity and that this phenotype will be reversed upon tumor regression. This will be assessed by characterizing the spatial organization, cell-cell interactions, activation/inhibition markers, and cytokine production of the main leukocyte lineages in situ over disease course. My preliminary data demonstrate that I can identify most of these major immune cell types at once within breast tumors, including subsets of macrophages, dendritic cells, and T cells. In addition, I found that two subsets of macrophages have differential localization: one which is intra-tumoral and another that is almost exclusively peritumoral. This peritumoral macrophage population closely interacts with T regulatory cells, which are important for immunosuppression in breast cancer. As such, I hypothesize that peritumoral FDMs spatially organize to interact with T regulatory cells via TCR-MHC II, thereby activating Tregs and skewing tumors toward an immunosuppressed microenvironment. To test this, I will use genetic mouse models to deplete these populations in a tumor stage-specific manner and assess the impact on tumor growth, survival, and response to clinical therapies. Overall, this proposal aims to understand the spatial dynamics of leukocytes in breast cancer, which will reveal key cell-cell interactions, organizational structures, and cellular communication networks that need to be disrupted/promoted in order to reengage antitumor immunity, facilitating the development of effective immunotherapies.

项目摘要 虽然免疫疗法彻底改变了某些恶性肿瘤的治疗方法，但尚未产生同样的效果 结果导致乳腺癌。这是惊人的，因为肿瘤内有大量的免疫细胞 影响疾病结果。有证据表明这些白细胞处于战略位置来执行它们的任务 功能，但对其在肿瘤进展和消退过程中的空间动态知之甚少。我的目标是 利用最新进展详细描述这些时空动力学的全面和机制图景 高维原位成像。我假设随着肿瘤的进展，免疫抑制细胞会阻断 促进抗肿瘤免疫的免疫细胞组织结构和细胞间通讯 这种表型将在肿瘤消退后逆转。这将通过表征空间特征来评估 主要白细胞的组织、细胞间相互作用、激活/抑制标记和细胞因子产生 病程中的原位谱系。我的初步数据表明我可以识别其中大部分专业 乳腺肿瘤内的免疫细胞类型，包括巨噬细胞、树突状细胞和 T 细胞亚群。 此外，我发现巨噬细胞的两个子集具有差异定位：一个是肿瘤内的 另一个几乎完全是瘤周的。这种瘤周巨噬细胞群密切相互作用 调节性 T 细胞对于乳腺癌的免疫抑制非常重要。因此，我假设 瘤周 FDM 在空间上组织通过 TCR-MHC II 与 T 调节细胞相互作用，从而激活 Tregs 和使肿瘤偏向免疫抑制的微环境。为了测试这一点，我将使用遗传 小鼠模型以肿瘤阶段特定的方式消除这些群体并评估对肿瘤的影响 生长、存活和对临床治疗的反应。总体而言，该提案旨在了解空间 乳腺癌中白细胞的动态，这将揭示关键的细胞间相互作用、组织结构、 和需要破坏/促进以重新发挥抗肿瘤作用的细胞通信网络 免疫，促进有效免疫疗法的开发。