Tissue engineering tools for monitoring the cellular and molecular response to therapy

摘要：三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌，治疗方法为

Summary: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that is treated with neoadjuvant therapy that targets both the primary tumor and systemic disease, with subsequent adjuvant immunotherapy. Even with the most cutting-edge therapeutic approach, approximately 20% of these patients, despite a pathologic complete response (pCR), have residual disease, present locally or in distal tissues, which may lead to disease recurrence either locally or within distal tissues. We have devised a novel technology – a scaffold that serves as a synthetic metastatic niche (MN) – that captures the systemic effects (i.e., immunological changes, tumor cells) of residual disease and could be employed to monitor for disease burden, progression, or regression. The pores of the scaffold allow for host cell infiltration and vascular ingrowth, with immune cells attracted to the implant based on a foreign body response. In a tumor-bearing mouse, the immune cells recruited to the implant are distinct from tumor-free mice, reflecting the changes observed in endogenous tissues (i.e., lung) because of systemic changes following cancer initiation and progression. These infiltrating immune cells precede the arrival of tumor cells, prepare the site for colonization, and facilitate disease progression. We propose that the scaffold can be used for longitudinal monitoring of disease following neoadjuvant and adjuvant immunotherapy. Disease monitoring is based on the molecular and cellular composition within the scaffold (e.g., immune cells or tumor cells) that reflect the systemic impacts of residual disease. The aims of the proposal include: Aim 1 will develop a prognostic signature that can determine response to neoadjuvant therapy and reflect the presence of residual disease. The scaffold will supplement the histological analysis of the primary site and can indicate the presence of residual disease through the systemic effects on cellular and molecular phenotypes in the scaffold. The scaffold analyses will be compared with histology of patient tissue, with the goal of identifying situations in which a pCR does not capture residual disease. In Aim 2, we propose to investigate the use of scaffolds for surveillance of recurrence and monitoring response during adjuvant therapy. We will also analyze the scaffold for the mechanisms that underlie the development of resistance to immune checkpoint blockade (ICB). Identification of residual disease typically occurs when patients self-report symptoms, indicating late-stage disease recurrence. Our platform overcomes this critical barrier by pre-defining a location to analyze for the systemic effects of disease. Collectively, these scaffolds provide a defined site in vivo to analyze that captures the systemic effects of residual disease on distant tissues. A solid organ, such as lung, cannot be readily monitored over time in a patient due to the morbidity of the procedure and early metastatic foci are small and difficult to detect within the total organ. Collectively, the scaffolds provide a tool to monitor for residual disease following neo-adjuvant or adjuvant therapy that is accessible with minimal risk, with the cellular and molecular analyses guiding individualized treatments with the potential to improve survival and reduce costs.