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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要尽管免疫疗法彻底改变了某些恶性肿瘤的治疗导致乳腺癌。鉴于有大量的肿瘤内免疫细胞，这是令人惊讶的影响疾病的结果。有证据表明，这些白细胞在战略上是为执行其执行的功能对肿瘤进展和回归方面的空间动力学知之甚少。我的目标详细介绍了这些时空动态的全面和机械图，并使用最新进展高维原位成像。我假设随着肿瘤的发展，免疫抑制细胞将阻塞免疫细胞组织结构和细胞电池通信，可促进抗肿瘤免疫，并该表型将在肿瘤回归后逆转。这将通过表征空间来评估主体白细胞的组织，细胞相互作用，激活/抑制标记和细胞因子产生谱系在疾病过程中原位。我的初步数据表明，我可以识别其中大多数专业免疫细胞在乳腺肿瘤中立即类型，包括巨噬细胞，树突状细胞和T细胞的子集。此外，我发现两个巨噬细胞的子集具有差异定位：一个是肿瘤内的而另一个几乎完全是腹膜。这种周围巨噬细胞种群紧密相互作用与T调节细胞有关，这对于乳腺癌的免疫抑制很重要。因此，我假设该周围FDM在空间上组织以通过TCR-MHC II与T调节细胞相互作用，从而激活 Tregs并将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异性的方式耗尽这些种群并评估对肿瘤的影响生长，生存和对临床疗法的反应。总体而言，该建议旨在了解空间乳腺癌中白细胞的动力学，这将揭示关键细胞 - 细胞相互作用，组织结构，以及需要破坏/促进才能重新接触抗肿瘤的蜂窝通信网络免疫，促进有效免疫疗法的发展。