新型口服辅助表位 WT1 蛋白疫苗在小鼠白血病模型中增强抗肿瘤活性。
Enhanced antitumor activity of a novel, oral, helper epitope-containing WT1 protein vaccine in a model of murine leukemia.
机构信息
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.
Department of Pediatrics, Osaka International Cancer Institute, Osaka, Japan.
出版信息
BMC Cancer. 2023 Feb 20;23(1):167. doi: 10.1186/s12885-023-10547-5.
BACKGROUND
A Wilms' tumor 1 (WT1) oral vaccine, Bifidobacterium longum (B. longum) 420, in which the bacterium is used as a vector for WT1 protein, triggers immune responses through cellular immunity consisting of cytotoxic T lymphocytes (CTLs) and other immunocompetent cells (e.g., helper T cells). We developed a novel, oral, helper epitope-containing WT1 protein vaccine (B. longum 2656) to examine whether or not B. longum 420/2656 combination further accelerates the CD4 T cell help-enhanced antitumor activity in a model of murine leukemia.
METHODS
C1498-murine WT1-a genetically-engineered, murine leukemia cell line to express murine WT1-was used as tumor cell. Female C57BL/6 J mice were allocated to the B. longum 420, 2656, and 420/2656 combination groups. The day of subcutaneous inoculation of tumor cells was considered as day 0, and successful engraftment was verified on day 7. The oral administration of the vaccine by gavage was initiated on day 8. Tumor volume, the frequency and phenotypes of WT1-specific CTLs in CD8 T cells in peripheral blood (PB) and tumor-infiltrating lymphocytes (TILs), as well as the proportion of interferon-gamma (INF-γ)-producing CD3CD4 T cells pulsed with WT1 peptide in splenocytes and TILs were determined.
RESULTS
Tumor volume was significantly smaller (p < 0.01) in the B. longum 420/2656 combination group than in the B. longum 420 group on day 24. WT1-specific CTL frequency in CD8 T cells in PB was significantly greater in the B. longum 420/2656 combination group than in the B. longum 420 group at weeks 4 (p < 0.05) and 6 (p < 0.01). The proportion of WT1-specific, effector memory CTLs in PB increased significantly in the B. longum 420/2656 combination group than in the B. longum 420 group at weeks 4 and 6 (p < 0.05 each). WT1-specific CTL frequency in intratumoral CD8 T cells and the proportion of IFN-γ-producing CD3CD4 T cells in intratumoral CD4 T cells increased significantly (p < 0.05 each) in the B. longum 420/2656 combination group than in the 420 group.
CONCLUSIONS
B. longum 420/2656 combination further accelerated antitumor activity that relies on WT1-specific CTLs in the tumor compared with B. longum 420.
背景
Wilms 瘤 1（WT1）口服疫苗，长双歧杆菌（B. longum）420，其中细菌被用作 WT1 蛋白的载体，通过细胞免疫触发免疫反应，包括细胞毒性 T 淋巴细胞（CTL）和其他免疫活性细胞（例如辅助 T 细胞）。我们开发了一种新型的口服辅助表位包含 WT1 蛋白疫苗（B. longum 2656），以检查长双歧杆菌 420/2656 联合是否进一步加速了在小鼠白血病模型中 CD4 T 细胞辅助增强抗肿瘤活性。
方法
C1498-小鼠 WT1-一种基因工程的、表达小鼠 WT1 的小鼠白血病细胞系，被用作肿瘤细胞。将雌性 C57BL/6 J 小鼠分配到长双歧杆菌 420、2656 和 420/2656 联合组。皮下接种肿瘤细胞的那一天被视为第 0 天，第 7 天验证成功植入。从第 8 天开始通过灌胃口服疫苗。测定肿瘤体积、外周血（PB）和肿瘤浸润淋巴细胞（TIL）中 CD8 T 细胞中 WT1 特异性 CTL 的频率和表型，以及脾细胞和 TIL 中与 WT1 肽脉冲的产生干扰素-γ（INF-γ）的 CD3CD4 T 细胞的比例。
结果
在第 24 天，长双歧杆菌 420/2656 联合组的肿瘤体积明显小于长双歧杆菌 420 组（p<0.01）。长双歧杆菌 420/2656 联合组在第 4 周（p<0.05）和第 6 周（p<0.01）时，WT1 特异性 CTL 在外周血 CD8 T 细胞中的频率明显大于长双歧杆菌 420 组。长双歧杆菌 420/2656 联合组在第 4 周和第 6 周时，WT1 特异性效应记忆 CTL 在 PB 中的比例明显高于长双歧杆菌 420 组（p<0.05）。长双歧杆菌 420/2656 联合组肿瘤内 CD8 T 细胞中 WT1 特异性 CTL 的频率和肿瘤内 CD4 T 细胞中 IFN-γ 产生的 CD3CD4 T 细胞的比例明显高于长双歧杆菌 420 组（p<0.05）。
结论
与长双歧杆菌 420 相比，长双歧杆菌 420/2656 联合进一步加速了依赖于肿瘤中 WT1 特异性 CTL 的抗肿瘤活性。
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