Sun Jingjing, Schiffman Jade, Raghunath Anitha, Ng Tang Derek, Chen Hong, Sharma Padmanee
Department of Genitourinary Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA.
Cancer Immun. 2008 May 27;8:9.
The cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule on T cells acts to maintain homeostasis by regulating the proliferation of recently activated T cells. Blockade of CTLA-4 by anti-CTLA-4 antibody enhances T cell responses and has elicited significant tumor regression in some cancer patients. Clinical trials are ongoing to investigate the efficacy of anti-CTLA-4 antibody as a cancer therapeutic. Reports from several clinical trials have documented the occurrence of adverse events in patients treated with anti-CTLA-4 antibody which have some similarities with autoimmune conditions and have been termed immune-related adverse events (irAEs). Most irAEs are reversible with corticosteroid therapy. Some investigators suggest that irAEs occur in the same patients who have anti-tumor responses as a result of the anti-CTLA-4 antibody. Immunologic mechanisms to explain why irAEs occur in some patients have not been reported. Here we report that bladder cancer patients treated with anti-CTLA-4 antibody have increased levels of the Th1 cytokine IFN-gamma detected in plasma samples. Although IFN-gamma is a potent anti-tumor and inflammatory cytokine, increased levels of IFN-gamma were not associated with irAEs in our patients. However, in one patient who experienced an irAE consisting of ischemic papillopathy and optic neuritis, we documented high pre-therapy levels of the Th2 cytokine IL-10 which decreased after treatment with anti-CTLA-4 antibody. The decrease in plasma IL-10 concentration coincided with the patient's irAE. We propose that decreased levels of IL-10 after treatment with anti-CTLA-4 therapy may be responsible for irAEs in some patients and needs to be further investigated in larger studies.
T细胞上的细胞毒性T淋巴细胞抗原4（CTLA-4）分子通过调节近期活化T细胞的增殖来维持体内平衡。抗CTLA-4抗体阻断CTLA-4可增强T细胞反应，并在一些癌症患者中引起显著的肿瘤消退。目前正在进行临床试验以研究抗CTLA-4抗体作为癌症治疗药物的疗效。几项临床试验的报告记录了接受抗CTLA-4抗体治疗的患者出现不良事件，这些事件与自身免疫性疾病有一些相似之处，被称为免疫相关不良事件（irAE）。大多数irAE用皮质类固醇治疗可逆转。一些研究人员认为，irAE发生在因抗CTLA-4抗体而产生抗肿瘤反应的同一患者中。尚未报道解释为何某些患者会出现irAE的免疫机制。在此我们报告，接受抗CTLA-4抗体治疗的膀胱癌患者血浆样本中检测到的Th1细胞因子干扰素-γ（IFN-γ）水平升高。尽管IFN-γ是一种有效的抗肿瘤和炎性细胞因子，但在我们的患者中，IFN-γ水平升高与irAE无关。然而，在一名经历了由缺血性视乳头病变和视神经炎组成的irAE的患者中，我们记录到其治疗前Th2细胞因子白细胞介素-10（IL-10）水平较高，在用抗CTLA-4抗体治疗后降低。血浆IL-10浓度的降低与该患者的irAE同时出现。我们提出，抗CTLA-4治疗后IL-10水平降低可能是某些患者发生irAE的原因，需要在更大规模的研究中进一步调查。
