Departments of Malignant Hematology, Drug Discovery, and Hematopathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Cancer Res. 2012 Sep 1;72(17):4440-8. doi: 10.1158/0008-5472.CAN-11-3619. Epub 2012 Jun 22.
Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell non-Hodgkin lymphomas. Although patients often respond initially to first-line treatment with chemotherapy plus monoclonal antibodies, relapse and decreased response to further lines of treatment eventually occurs. Harnessing the immune system to elicit its exquisite specificity and long-lasting protection might provide sustained MCL immunity that could potentially eradicate residual malignant cells responsible for disease relapse. Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4(+) T cells and restoration of responsiveness of tolerized T cells. In addition, treatment of MCL-bearing mice with a specific Stat3 inhibitor resulted in decreased Stat3 phosphorylation in malignant B cells and anti-lymphoma immunity in vivo. Our findings therefore indicate that Stat3 inhibition may represent a therapeutic strategy to overcome tolerance to tumor antigens and elicit a strong immunity against MCL and other B-cell malignancies.
套细胞淋巴瘤（MCL）是一种侵袭性和不可治愈的 B 细胞非霍奇金淋巴瘤亚型。尽管患者通常最初对化疗加单克隆抗体的一线治疗有反应，但最终会发生复发和对进一步治疗线的反应降低。利用免疫系统来激发其卓越的特异性和持久的保护作用，可能会提供持续的 MCL 免疫力，从而有可能根除导致疾病复发的残留恶性细胞。在这里，我们表明，在恶性 B 细胞中遗传或药理学破坏 Stat3 会增强其免疫原性，从而更好地激活抗原特异性 CD4(+)T 细胞，并恢复耐受 T 细胞的反应性。此外，用特异性 Stat3 抑制剂治疗患有 MCL 的小鼠会导致恶性 B 细胞中 Stat3 磷酸化减少和体内抗淋巴瘤免疫。因此，我们的研究结果表明，Stat3 抑制可能代表一种克服对肿瘤抗原的耐受并引发针对 MCL 和其他 B 细胞恶性肿瘤的强大免疫的治疗策略。
