肿瘤细胞治疗研究
英文原题：Collagen-Binding IL-15 Immunocytokine Armed Oncolytic Adenovirus Establishes a Self-Reinforcing Immunostimulatory Milieu to Potentiate Antitumor Immunity.
免疫抑制微环境限制了三阴性乳腺癌（TNBC）的免疫治疗。
免疫抑制微环境限制了三阴性乳腺癌（TNBC）的免疫治疗。白细胞介素-15（IL-15）可激活细胞毒性淋巴细胞，但受限于快速清除和肿瘤滞留不良。在此，我们开发了一种编码IL15C-CBD的溶瘤腺病毒，IL15C-CBD是一种免疫细胞因子，由IL-15/IL-15Rα sushi结构域复合物与胶原结合结构域融合而成，从而在肿瘤内建立自我强化的免疫刺激环境。瘤内注射OV-IL15C-CBD可裂解肿瘤细胞并分泌IL15C-CBD，后者锚定于细胞外基质胶原，形成局部细胞因子储库。在小鼠4T1 TNBC模型中，该策略通过招募CD8+ T细胞和NK 细胞、耗竭调节性T细胞以及将巨噬细胞极化为M1样表型，深刻重塑了微环境。因此，OV-IL15C-CBD诱导了显著的肿瘤消退并延长了生存期，且无明显全身毒性。这一治疗优势在EMT6乳腺肿瘤模型中进一步得到验证，产生了一致的抗肿瘤疗效和延长的生存期。总之，通过溶瘤病毒将免疫细胞因子锚定于肿瘤基质，为TNBC提供了一种潜在安全有效的局部免疫治疗。
The immunosuppressive microenvironment limits immunotherapy in triple-negative breast cancer (TNBC). Interleukin-15 (IL-15) activates cytotoxic lymphocytes but is limited by rapid clearance and poor tumor retention. Here, we developed an oncolytic adenovirus encoding IL15C-CBD, an immunocytokine comprising an IL-15/IL-15Rα sushi-domain complex fused to a collagen-binding domain, thereby establishing a self-reinforcing immunostimulatory milieu within tumors. Intratumoral administered OV-IL15C-CBD lyses tumor cells and secretes IL15C-CBD that anchors to extracellular matrix collagens, forming a localized cytokine reservoir. In the murine 4T1 TNBC model, this strategy profoundly remodeled the microenvironment by recruiting CD8 + T cells and natural killer cells, depleting regulatory T cells, and polarizing macrophages. toward an M1-like phenotype. Consequently, OV-IL15C-CBD induced significant tumor regression and extended survival without evident systemic toxicity. This therapeutic advantage was further validated in the EMT6 breast tumor model, yielding consistent antitumor efficacy and prolonged survival. Collectively, anchoring immunocytokines to the tumor stroma via oncolytic viruses provides a potentially safe and effective localized immunotherapy for TNBC.
MEMBER ACCOUNT
登录成功会直接打开下一页。
