PO.IM01.08 · 免疫学
间歇性环磷酰胺和长春瑞滨联合抗PD-1在TNBC小鼠模型中诱导可转移的T细胞介导的抗肿瘤免疫和长期记忆
Intermittent cyclophosphamide and vinorelbine combined with anti-PD-1 induce transferable T-cell-mediated antitumor immunity and long-term memory in TNBC mouse models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
基于细胞的免疫疗法为利用治疗诱导的抗肿瘤免疫实现持久的肿瘤控制提供了一种强有力的手段。我们此前开发了一种三联疗法(TT)方案，将长春瑞滨介导的抗原呈递细胞(APC)激活与环磷酰胺驱动的TCF1⁺干细胞样T细胞(scT)诱导相结合，显著增强了抗PD-1在耐药肿瘤模型中的疗效。TT方案包括每六天给予三次间歇剂量的长春瑞滨和环磷酰胺，同时每两天给予五次抗PD-1剂量。在非霍奇金淋巴瘤(NHL)模型中，TT不仅实现了强劲的肿瘤消退，还赋予了长期免疫记忆，其证据是肿瘤再攻击时的保护作用。将这些发现扩展到三阴性乳腺癌(TNBC)，TT诱导了相当的抗肿瘤活性。为确定TT引发的免疫是否可过继转移，用TT处理携带4T1 TNBC的免疫健全BALB/c小鼠，并收集包括血液、脾脏和淋巴结在内的免疫组织，转移到接种相同肿瘤的同基因BALB/c裸鼠中。引人注目的是，转移来自TT处理供者的外周血显著延迟了肿瘤生长，表明循环免疫细胞足以传递保护作用。相比之下，淋巴细胞清除消除了这种效应。通过流式细胞分选或使用中和抗体选择性清除CD4⁺或CD8⁺ T细胞也消除了治疗获益，证实了它们在可转移抗肿瘤应答中的重要作用。总之，这些发现表明，TT诱导了能够介导细胞可转移肿瘤控制的全身性、形成记忆的T细胞应答。目前的工作重点是鉴定TT诱导的T细胞所识别的肿瘤抗原，最终目标是开发靶向治疗性疫苗，将这些获益扩展到更广泛的患者人群。
查看英文原文 English abstract
Cell-based immunotherapies offer a powerful means to harness treatment-induced antitumor immunity for durable tumor control. We previously developed a Triple-Therapy (TT) regimen combining vinorelbine-mediated activation of antigen-presenting cells (APCs) with cyclophosphamide-driven induction of TCF1⁺ stem-cell-like T cells (scTs), markedly enhancing anti-PD-1 efficacy in resistant tumor models. The TT protocol consists of three intermittent doses of vinorelbine, and cyclophosphamide administered every six days, together with five anti-PD-1 doses delivered every two days.In a Non-Hodgkin Lymphoma (NHL) model, TT not only achieved strong tumor regression but also conferred long-term immunological memory, as evidenced by protection upon tumor rechallenge. Extending these findings to triple-negative breast cancer (TNBC), TT induced comparable antitumor activity. To determine whether TT-elicited immunity could be adoptively transferred, immunocompetent BALB/c mice bearing 4T1 TNBC were treated with TT, and immune tissues-including blood, spleen, and lymph nodes-were collected and transferred into syngeneic BALB/c nude mice inoculated with the same tumor.Strikingly, transfer of peripheral blood from TT-treated donors significantly delayed tumor growth, indicating that circulating immune cells are sufficient to convey protection. In contrast, lymphocyte depletion abolished this effect. Selective ablation of CD4⁺ or CD8⁺ T cells-performed either by flow cytometric sorting or using neutralizing antibodies-also eliminated the therapeutic benefit, confirming their essential role in the transferable antitumor response.Overall, these findings demonstrate that TT induces systemic, memory-forming T-cell responses capable of mediating cell-transferable tumor control. Current work focuses on identifying the tumor antigens recognized by TT-induced T cells, with the ultimate goal of developing targeted therapeutic vaccines to extend these benefits to broader patient populations.
利益披露 Disclosure
D. Lorenzo, None..
A. Vaccari, None..
P. Nistico', None..
P. Falvo, None.