PO.CL05.05 · 临床研究
一种纳米药物在乳腺癌模型中诱导的定量和功能性免疫重编程
Quantitative and functional immune reprogramming induced by a nanomedicine in breast cancer model
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
纳米颗粒(NP)正成为肿瘤学中一种有前景的策略，可优化药物递送并具有调节免疫反应的潜力。在本研究中，我们开发了一种创新的纳米颗粒，包封docetaxel并用trastuzumab功能化，以精确靶向HER2阳性肿瘤(称为ANC，即抗体纳米颗粒偶联物)。免疫调节效应在C57BL/6小鼠中进行，分别通过腹腔注射给予游离docetaxel(1.6 mg/kg)和trastuzumab(135 ng/kg)(n=29)或ANC(纳米颗粒中docetaxel和trastuzumab剂量与游离药物相同，n=40)。在血液(J0-J21)和肿瘤组织(J21)中进行免疫分析，以评估参与抗肿瘤免疫的主要淋巴系和髓系亚群的定量和功能变化。流式细胞术分析包括B细胞、T细胞(CD4⁺、CD8⁺)、活化T细胞亚群、NK细胞、调节性T细胞(Treg)、髓源性抑制细胞(MDSC)和调节性B细胞(Breg)。在血液中，各组间B细胞、NK细胞、CD4⁺或CD8⁺ T细胞及其活化亚群均未观察到显著差异。与对照组相比，ANC组检测到Treg频率有降低趋势(p=0.053)，提示免疫抑制活性的早期全身性调节。所有组间MDSC水平保持不变。在肿瘤中，各组间总体B细胞水平相当，但ANC治疗的小鼠显示Breg比例增加，提示潜在的局部免疫抑制。ANC组NK细胞浸润和活化趋于更高(p≈0.08)，提示局部免疫刺激。CD4⁺ T细胞未检测到差异，而在ANC治疗的肿瘤中观察到CD8⁺ T细胞频率降低。Treg水平也显示出下降趋势(p=0.07)，与肿瘤微环境内免疫调节压力的部分降低一致。各条件间MDSC水平无显著差异。ANC制剂表现出微妙但具有生物学相关性的免疫调节趋势，包括肿瘤内Treg频率降低和活化NK细胞增加，可能有利于抗肿瘤反应。相反，ANC治疗肿瘤中升高的Breg群体可能通过促进局部免疫抑制而抵消这些效应。这些发现提示ANC可能在不引起重大全身性改变的情况下微调肿瘤免疫格局。需要通过扩大队列和功能性检测进行进一步研究，以确认这些趋势并阐明其对治疗疗效的意义。
查看英文原文 English abstract
Nanoparticles (NPs) are emerging as a promising strategy in oncology, offering optimised drug delivery and the potential to modulate immune responses. In this study, we developed an innovative nanoparticle encapsulating docetaxel and functionalised with trastuzumab for precise targeting of HER2-positive tumours (called ANC for Antibody Nanoparticle Conjugate). Immunomodulatory effects were performed in C57BL/6 mice administered free docetaxel (1.6 mg-kg-¹) and trastuzumab (135 ng-kg-¹) by intraperitoneal injection (n = 29) or ANC (nanoparticles at the same docetaxel and trastuzumab doses as the free drugs, n = 40). Immune profiling was performed in blood (J0-J21) and tumor tissue (J21) to evaluate quantitative and functional changes in major lymphoid and myeloid subsets involved in antitumor immunity. Flow cytometric analyses included B cells, T cells (CD4⁺, CD8⁺), activated T-cell subsets, NK cells, regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and regulatory B cells (Breg). In blood, no significant differences were observed between groups for B cells, NK cells, CD4⁺ or CD8⁺ T cells, or their activated subsets. A trend toward reduced Treg frequencies was detected in the ANC group compared with controls (p = 0.053), suggesting early systemic modulation of immunosuppressive activity. MDSC levels remained unchanged across all groups. In tumors, global B-cell levels were comparable between groups, but ANC-treated mice showed an increased proportion of Breg, indicating a potential local immunosuppression. NK-cell infiltration and activation tended to be higher in the ANC group (p ≈ 0.08), suggesting localized immune stimulation. No differences were detected for CD4⁺ T cells, whereas a reduction in CD8⁺ T-cell frequency was observed in ANC-treated tumors. Treg levels also showed a decreasing trend (p = 0.07), consistent with a partial reduction in immunoregulatory pressure within the tumor microenvironment. MDSC levels did not differ significantly between conditions. ANC formulation exhibited subtle yet biologically relevant immunomodulatory trends, including reduced Treg frequencies and increased activated NK cells within the tumor, potentially favoring antitumor responses. Conversely, the elevated Breg population in ANC-treated tumors may counterbalance these effects by promoting local immunosuppression. These findings suggest that ANC may fine-tune the tumor immune landscape without inducing major systemic alterations. Further investigation with extended cohorts and functional assays will be required to confirm these trends and clarify their implications for therapeutic efficacy.
利益披露 Disclosure
M. Dacos, None..
L. Plantureux, None..
S. Giacometti, None..
J. Ciccolini, None..
R. Fanciullino, None.