Department of Gynecology and Obstetrics, University Hospital of Heidelberg, Voßstraße 9, 69115 Heidelberg, Germany.
Cancer Immunol Immunother. 2011 Mar;60(3):401-11. doi: 10.1007/s00262-010-0956-4. Epub 2010 Dec 14.
A wide variety of cancer types has been associated with paraneoplastic autoimmune disorders and with the induction of autoimmunity against several autoantigens, among them self-antigens that are also expressed by tumor cells. This raises the question of autoimmune disorders as a result of immune reactions to the tumor. To date, however, requirements for the generation of autoimmune reactions in cancer patients remain largely unclear. In this study, we characterized conditions in altogether 131 patients, which determine autoimmune responses in primary breast cancer patients. We used ex vivo IFN-γ EliSpot assays against autologous tumor or skin lysates to evaluate tumor- and auto-reactive T-cells (TCs) in the bone marrow (BM) as well as ELISA, ECLIA, and turbidimetric immunoassays for the detection of auto-reactive antibodies in the peripheral blood and compared results to intratumoral cytokine concentrations and pathobiological features of the primary tumor tissue. We here demonstrate a significant correlation between anti-tumor BMTC responses and cellular autoimmune reactivity in primary breast cancer patients (P = 0.002). Humoral autoimmune reactions, however, were negatively correlated with anti-tumor TC immunity (P = 0.039). We observed auto-reactive BMTCs especially in patients with well-differentiated, hormone receptor-positive carcinomas (P = 0.009). Furthermore, elevated concentrations of intratumoral IFN-α significantly correlated with the induction of cellular autoimmune reactivity (P = 0.0002), while humoral autoimmune reactions correlated with increased levels of intratumoral IL-12 (P = 0.04). Altogether, these data indicate a significant role of the tumor microenvironment and particularly that of IFN-α and IL-12 in the induction of systemic autoimmune responses and imply that the primary tumor tissue represents an integral site of autoimmune regulation in cancer patients.
多种癌症类型与副肿瘤自身免疫性疾病相关，并导致针对多种自身抗原的自身免疫，其中包括肿瘤细胞也表达的自身抗原。这就提出了一个问题，即自身免疫性疾病是否是由于对肿瘤的免疫反应引起的。然而，迄今为止，癌症患者中自身免疫反应的产生要求在很大程度上仍不清楚。在这项研究中，我们对总共 131 名患者的情况进行了特征描述，这些情况决定了原发性乳腺癌患者的自身免疫反应。我们使用针对自体肿瘤或皮肤裂解物的体外 IFN-γ Elispot 测定法来评估骨髓中的肿瘤和自身反应性 T 细胞（TC），并使用 ELISA、ECLIA 和浊度免疫测定法检测外周血中的自身反应性抗体，并将结果与肿瘤内细胞因子浓度和原发性肿瘤组织的病理生物学特征进行比较。我们在此证明，原发性乳腺癌患者的抗肿瘤 BMTC 反应与细胞自身免疫反应之间存在显著相关性（P = 0.002）。然而，体液自身免疫反应与抗肿瘤 TC 免疫呈负相关（P = 0.039）。我们观察到自身反应性 BMTC 尤其存在于分化良好、激素受体阳性的癌患者中（P = 0.009）。此外，肿瘤内 IFN-α浓度的升高与细胞自身免疫反应的诱导显著相关（P = 0.0002），而体液自身免疫反应与肿瘤内 IL-12 水平的升高相关（P = 0.04）。总的来说，这些数据表明肿瘤微环境，特别是 IFN-α和 IL-12 的作用在诱导系统性自身免疫反应中具有重要作用，并暗示原发性肿瘤组织是癌症患者自身免疫调节的一个完整部位。
