Dipartimento di Scienze Biomediche e Cliniche, Università di Milano, Milan, 20157, Italy.
Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
J Nanobiotechnology. 2024 Apr 15;22(1):184. doi: 10.1186/s12951-024-02441-4.
Despite the advent of numerous targeted therapies in clinical practice, anthracyclines, including doxorubicin (DOX), continue to play a pivotal role in breast cancer (BC) treatment. DOX directly disrupts DNA replication, demonstrating remarkable efficacy against BC cells. However, its non-specificity toward cancer cells leads to significant side effects, limiting its clinical utility. Interestingly, DOX can also enhance the antitumor immune response by promoting immunogenic cell death in BC cells, thereby facilitating the presentation of tumor antigens to the adaptive immune system. However, the generation of an adaptive immune response involves highly proliferative processes, which may be adversely affected by DOX-induced cytotoxicity. Therefore, understanding the impact of DOX on dividing T cells becomes crucial, to deepen our understanding and potentially devise strategies to shield anti-tumor immunity from DOX-induced toxicity. Our investigation focused on studying DOX uptake and its effects on human lymphocytes. We collected lymphocytes from healthy donors and BC patients undergoing neoadjuvant chemotherapy (NAC). Notably, patient-derived peripheral blood mononuclear cells (PBMC) promptly internalized DOX when incubated in vitro or isolated immediately after NAC. These DOX-treated PBMCs exhibited significant proliferative impairment compared to untreated cells or those isolated before treatment initiation. Intriguingly, among diverse lymphocyte sub-populations, CD8 + T cells exhibited the highest uptake of DOX. To address this concern, we explored a novel DOX formulation encapsulated in ferritin nanocages (FerOX). FerOX specifically targets tumors and effectively eradicates BC both in vitro and in vivo. Remarkably, only T cells treated with FerOX exhibited reduced DOX internalization, potentially minimizing cytotoxic effects on adaptive immunity.Our findings underscore the importance of optimizing DOX delivery to enhance its antitumor efficacy while minimizing adverse effects, highlighting the pivotal role played by FerOX in mitigating DOX-induced toxicity towards T-cells, thereby positioning it as a promising DOX formulation. This study contributes valuable insights to modern cancer therapy and immunomodulation.
尽管在临床实践中出现了许多靶向治疗方法，但包括多柔比星（DOX）在内的蒽环类药物在乳腺癌（BC）治疗中仍然发挥着关键作用。DOX 直接破坏 DNA 复制，对 BC 细胞表现出显著的疗效。然而，其对癌细胞的非特异性导致严重的副作用，限制了其临床应用。有趣的是，DOX 还可以通过促进 BC 细胞中的免疫原性细胞死亡来增强抗肿瘤免疫反应，从而促进肿瘤抗原向适应性免疫系统的呈递。然而，适应性免疫反应的产生涉及高度增殖的过程，这可能会受到 DOX 诱导的细胞毒性的不利影响。因此，了解 DOX 对分裂 T 细胞的影响变得至关重要，这有助于加深我们的理解，并有可能设计策略来保护抗肿瘤免疫免受 DOX 诱导的毒性。我们的研究重点是研究 DOX 的摄取及其对人淋巴细胞的影响。我们从健康供体和接受新辅助化疗（NAC）的 BC 患者中收集淋巴细胞。值得注意的是，当在体外孵育或在 NAC 后立即分离时，源自患者的外周血单核细胞（PBMC）迅速摄取 DOX。与未经处理的细胞或治疗前分离的细胞相比，这些 DOX 处理的 PBMC 表现出明显的增殖受损。有趣的是，在各种淋巴细胞亚群中，CD8+T 细胞对 DOX 的摄取最高。为了解决这个问题，我们探索了一种新型 DOX 制剂，该制剂封装在铁蛋白纳米笼（FerOX）中。FerOX 特异性靶向肿瘤，并在体外和体内有效根除 BC。值得注意的是，只有用 FerOX 处理的 T 细胞表现出 DOX 摄取减少，从而最大程度地减少了对适应性免疫的细胞毒性作用。我们的发现强调了优化 DOX 递送以增强其抗肿瘤疗效同时最小化不良反应的重要性，突出了 FerOX 在减轻 DOX 对 T 细胞的毒性方面的关键作用，从而将其定位为一种有前途的 DOX 制剂。这项研究为现代癌症治疗和免疫调节提供了有价值的见解。
