An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy
An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy
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IgG4 在癌症中发挥重要作用的免疫逃避机制及其对免疫治疗的启示
DOI：
10.1136/jitc-2020-000661
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Gu, Jiang
中科院分区：
文献类型：
--
作者：
Wang, Hui;Xu, Qian;Gu, Jiang
背景近年来，癌症免疫治疗取得了令人印象深刻的进展，这在很大程度上源于细胞免疫。体液免疫在癌症发生中的作用还知之甚少。根据我们以前的观察，我们假设免疫球蛋白亚型IgG4在癌症免疫逃避中发挥重要作用。方法采用人肿瘤标本和动物肿瘤模型，采用多种体外和体内实验技术，对IgG4的分布、丰度、作用、性质和可能的机制进行研究。结果在一组食道癌患者中，发现癌组织中含IgG4的B淋巴细胞和IgG4浓度明显升高，血清中IgG4浓度也明显升高。两者都与癌症恶性程度增加和预后不良呈正相关，也就是说，更多的IgG4似乎与更具侵袭性的癌症生长有关。我们进一步发现，无论其抗原特异性如何，IgG4在体外都能抑制抗体依赖细胞介导的细胞毒作用、抗体依赖细胞吞噬作用和补体依赖细胞毒作用等经典免疫反应，这些作用是通过其Fc片段与癌症特异性IgG1的Fc片段结合而获得的。我们还发现，在免疫效应细胞的Fc受体反应中，IgG4与IgG1竞争。因此，肿瘤微环境中局部升高的IgG4可抑制抗体介导的抗癌反应，帮助肿瘤逃避局部免疫攻击，间接促进肿瘤生长。这一假设在三种不同的免疫效力小鼠模型中得到了验证。我们发现，局部应用IgG4显著加速了接种的乳腺癌和结直肠癌以及致癌物诱导的皮肤乳头状瘤的生长。我们还测试了用于癌症免疫治疗的抗体药物nivolumab，它本质上是IgG4，具有稳定的S228P突变，发现它显著促进了小鼠的癌症生长。这可能为新出现的超进性疾病提供了一种解释，有时与癌症免疫治疗有关。结论可能存在一种未知的免疫逃逸机制，其中IgG4在肿瘤微环境中起重要作用，对肿瘤的诊断和免疫治疗具有重要意义。
Background Recent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion. Methods The distribution, abundance, actions, properties and possible mechanisms of IgG4 were investigated with human cancer samples and animal tumor models with an extensive array of techniques both in vitro and in vivo. Results In a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells in vitro, and these effects were obtained through its Fc fragment reacting to the Fc fragments of cancer-specific IgG1 that has been bound to cancer antigens. We also found that IgG4 competed with IgG1 in reacting to Fc receptors of immune effector cells. Therefore, locally increased IgG4 in cancer microenvironment should inhibit antibody-mediated anticancer responses and help cancer to evade local immune attack and indirectly promote cancer growth. This hypothesis was verified in three different immune potent mouse models. We found that local application of IgG4 significantly accelerated growth of inoculated breast and colorectal cancers and carcinogen-induced skin papilloma. We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice. This may provide an explanation to the newly appeared hyperprogressive disease sometimes associated with cancer immunotherapy. Conclusion There appears to be a previously unrecognized immune evasion mechanism with IgG4 playing an essential role in cancer microenvironment with implications in cancer diagnosis and immunotherapy.