Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, Jiangsu, China.
Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, Jiangsu, China.
Int Immunopharmacol. 2020 Aug;85:106631. doi: 10.1016/j.intimp.2020.106631. Epub 2020 May 26.
Increasing knowledge of colorectal cancer stem cells (CCSCs) and tumor microenvironment improves our understanding of cellular mechanisms involved in the immunity against colorectal cancer (CRC). Tumor associated antigens were evaluated via RNA-seq and bioinformatics analysis, evoking promising targets for tumor immunotherapy. MUC1 has been demonstrated to participate in the maintenance, tumorigenicity, glycosylation and metastasis of CCSCs, which may provide a new priority for CSC vaccination. In the present study, the vaccination with CCSCs with high expression of MUC1 was evaluated in a murine model for the vaccine's immunogenicity and protective efficacy against CRC. CD133 CCSCs were isolated from SW620 cell line using a magnetic-activated cell sorting system, and shMUC1 was further used to knock down the expression of MUC1 in CD133 CCSCs. Mice were subcutaneously immunized with the cell lysates of CCSCs and shMUC1 CCSCs, followed by a challenge with SW620 cells at ten days after final vaccination. The results indicated CCSC vaccine significantly reduced the tumor growth via a target killing of CCSCs as evidenced by a decrease of CD133 cells and ALDH cells in tumors. Moreover, CCSC vaccine resulted in the elevated NK cytotoxicity, production of perforin, granzyme B, IFN-γ, memory B cells, and anti-MUC1 antibodies. Of note, MUC1 knockdown partly impaired the anti-tumor efficacy of CCSC vaccine. Importantly, the CCSC vaccine has no toxic damage to organs. Overall, CCSC vaccine could serve as a potent and safe vaccine for CRC treatment, and MUC1 might play an essential role in CCSC vaccine.
越来越多的结直肠癌干细胞（CCSCs）和肿瘤微环境的知识提高了我们对细胞机制的理解，这些细胞机制参与了结直肠癌（CRC）的免疫。通过 RNA-seq 和生物信息学分析评估肿瘤相关抗原，为肿瘤免疫治疗引发了有希望的靶点。MUC1 已被证明参与 CCSCs 的维持、致瘤性、糖基化和转移，这可能为 CSC 疫苗接种提供新的优先事项。在本研究中，在小鼠模型中评估了高表达 MUC1 的 CCSC 疫苗的免疫原性和对 CRC 的保护效力。使用磁激活细胞分选系统从 SW620 细胞系中分离 CD133 CCSC，并进一步使用 shMUC1 敲低 CD133 CCSC 中的 MUC1 表达。用 CCSC 和 shMUC1 CCSC 的细胞裂解物皮下免疫小鼠，最后一次接种后 10 天用 SW620 细胞进行挑战。结果表明，CCSC 疫苗通过靶向杀伤 CCSC 显著抑制肿瘤生长，这表现为肿瘤中 CD133 细胞和 ALDH 细胞减少。此外，CCSC 疫苗导致 NK 细胞毒性、穿孔素、颗粒酶 B、IFN-γ、记忆 B 细胞和抗 MUC1 抗体的产生增加。值得注意的是，MUC1 敲低部分损害了 CCSC 疫苗的抗肿瘤功效。重要的是，CCSC 疫苗对器官没有毒性损伤。总之，CCSC 疫苗可作为 CRC 治疗的有效且安全的疫苗，MUC1 可能在 CCSC 疫苗中发挥重要作用。
