Schrack Ian A, Pereles Rebecca S, Ross Brian C, Ma Jeffrey A, Urie Russell R, Irish Emily R, Escalona Guillermo, Griffin Kate V, Kang Kathryn, Jeruss Jacqueline S, Shea Lonnie D
Department of Biomedical Engineering, University of Michigan, Ann Arbor; MI, 48109, USA.
Department of Surgery University of Michigan, Ann Arbor; MI, 48109, USA.
Immunomedicine. 2024 Dec;4(2). doi: 10.1002/imed.70000. Epub 2025 Jun 9.
Metastatic triple negative breast cancer poses a significant health challenge due to rapid progression and limited treatment options. Immunotherapies targeting T cell responses against metastatic tumors depend on the presence of specific T cell phenotypes, which dynamically evolve with disease progression and treatment. Herein, we investigate T cell phenotype dynamics throughout metastatic disease progression, focusing on both the metastatic site in the lung and a biomaterial implant that serves as a synthetic metastatic niche, with the latter providing an accessible, non-vital tissue for longitudinal analysis. Regulatory T cells were reduced at the lung and scaffold implant sites of metastasis following disease onset and progression relative to healthy mice, while Th1 and Th17 populations remained relatively stable. CD8+ T cells transitioned from naïve and central memory to effector memory with disease progression. Additionally, functional analyses involving the metastatic tissues suggested the primary T cell suppressive mechanisms was reduced migration, with no impact on T cell activation. Blood-based analyses demonstrated some of these phenotypic dynamics yet does not recapitulate the functional assays. Collectively, the scaffold provides a platform for dynamically monitoring T cell phenotypes and functions similar to the metastatic lung, enabling longitudinal monitoring of disease progression that could stratify patient populations.
转移性三阴性乳腺癌因其快速进展和有限的治疗选择而对健康构成重大挑战。针对转移性肿瘤的T细胞反应的免疫疗法取决于特定T细胞表型的存在,这些表型会随着疾病进展和治疗而动态演变。在此,我们研究了转移性疾病进展过程中T细胞表型的动态变化,重点关注肺部的转移部位以及作为合成转移微环境的生物材料植入物,后者为纵向分析提供了一个可及的、非生命的组织。与健康小鼠相比,疾病发生和进展后,转移性肺和支架植入部位的调节性T细胞减少,而Th1和Th17细胞群相对保持稳定。随着疾病进展,CD8 + T细胞从初始和中枢记忆状态转变为效应记忆状态。此外,对转移组织的功能分析表明,主要的T细胞抑制机制是迁移减少,而对T细胞激活没有影响。基于血液的分析显示了其中一些表型动态变化,但无法重现功能检测结果。总体而言,该支架为动态监测类似于转移性肺的T细胞表型和功能提供了一个平台,能够对疾病进展进行纵向监测,从而对患者群体进行分层。