Xu Qian, Zhang Zaiping, Chen Zhiming, Zhang Biying, Zhao Chanyuan, Zhang Yimin, Zhao Conghui, Deng Xiaodong, Zhou Yao, Wu Yanyun, Gu Jiang
Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Shantou University Medical College, Shantou 515041, Guangdong, China,
Department of Pathology, Beijing University Health Science Center, Beijing 100083, China,
Cancer Manag Res. 2019 Mar 7;11:2073-2085. doi: 10.2147/CMAR.S188172. eCollection 2019.
Previous accidental findings showed that administration of immunoglobulin G (IgG) in treating autoimmune diseases was able to inhibit cancers that happened to grow in these patients. However, such treatment has not been used to treat cancer patients clinically. The mechanism and optimal dosages of this treatment have not been established. Subsequent animal experiments confirmed this effect, but all previous studies in animal models used human IgG which was heterogeneous to the animal hosts and therefore could adversely interfere with the results.
We tested different dosages of mouse IgG in treating and preventing three syngeneic cancer types (melanoma, colon cancer, and breast cancer) in three immune potent mouse models. The expression of Ki67, CD34, VEGF, MMPs, and cytokines in tumor tissues were examined with immunohistochemistry or quantitative real-time PCR to evaluate tumor proliferation, vascularization, metastasis, and proinflammatory response in the tumor microenvironment.
We found that low-dose IgG could effectively inhibit cancer progression, regulate tumor vessel normalization, and prolong survival. Administration of IgG before cancer cell inoculation could also prevent the development of cancer. In addition, IgG caused changes in a number of cytokines and skewed macrophage polarization toward M1-like phenotype, characterized by proinflammatory activity and inhibition of proliferation of cancer cells.
Our findings suggest that nonspecific IgG at low dosages could be a promising candidate for cancer prevention and treatment.
既往偶然发现,在治疗自身免疫性疾病时给予免疫球蛋白G(IgG)能够抑制恰巧在这些患者体内生长的癌症。然而,这种治疗方法尚未在临床上用于治疗癌症患者。该治疗方法的机制和最佳剂量尚未确定。随后的动物实验证实了这种效果,但此前在动物模型中的所有研究都使用了与人源宿主不同源的人IgG,因此可能会对结果产生不利干扰。
我们在三种免疫功能正常的小鼠模型中测试了不同剂量的小鼠IgG对三种同基因癌症类型(黑色素瘤、结肠癌和乳腺癌)的治疗和预防效果。通过免疫组织化学或定量实时PCR检测肿瘤组织中Ki67、CD34、血管内皮生长因子(VEGF)、基质金属蛋白酶(MMPs)和细胞因子的表达,以评估肿瘤增殖、血管生成、转移以及肿瘤微环境中的促炎反应。
我们发现低剂量IgG可有效抑制癌症进展,调节肿瘤血管正常化,并延长生存期。在接种癌细胞前给予IgG还可预防癌症的发生。此外,IgG引起多种细胞因子的变化,并使巨噬细胞极化倾向于M1样表型,其特征为具有促炎活性并抑制癌细胞增殖。
我们的研究结果表明,低剂量的非特异性IgG可能是一种有前景的癌症预防和治疗候选药物。