Investigating the Spatial Dynamics of Intratumoral Immune Cells in Breast Cancer

项目摘要 虽然免疫疗法已经彻底改变了某些恶性肿瘤的治疗，但它还没有产生同样的效果。 会导致乳腺癌这是惊人的，因为有大量的肿瘤内免疫细胞， 影响疾病结果。有证据表明，这些白细胞的战略地位，以执行其 功能，但对它们在肿瘤进展和消退中的空间动力学知之甚少。我的目标是 详细介绍了这些时空动态的综合和机械的图片使用最近的进展， 高维原位成像我假设随着肿瘤的发展，免疫抑制细胞会阻止 免疫细胞组织结构和细胞间通讯，促进抗肿瘤免疫， 这种表型将在肿瘤消退时逆转。这将通过表征空间 主要白细胞的组织、细胞-细胞相互作用、激活/抑制标记物和细胞因子产生 在疾病过程中原位的谱系。我的初步数据表明，我可以识别这些主要的 在乳腺肿瘤中，免疫细胞类型，包括巨噬细胞，树突状细胞和T细胞的子集。 此外，我发现两个亚群的巨噬细胞具有不同的定位：一个是在肿瘤内 另一种几乎完全是瘤周的。这种肿瘤周围巨噬细胞群与肿瘤周围的 调节性T细胞，这对乳腺癌的免疫抑制很重要。因此，我假设 肿瘤周围的FDM在空间上组织起来，通过TCR-MHC II与T调节细胞相互作用，从而激活 使肿瘤倾向于免疫抑制的微环境。为了验证这一点，我将使用遗传 小鼠模型，以肿瘤阶段特异性方式消耗这些群体，并评估对肿瘤的影响 生长、存活和对临床治疗的反应。总的来说，这项建议旨在了解空间 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， 和细胞通讯网络，需要被破坏/促进，以重新参与抗肿瘤 免疫，促进有效免疫疗法的发展。

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.