Long-lasting complete regression of established mouse tumors by counteracting Th2 inflammation.
Long-lasting complete regression of established mouse tumors by counteracting Th2 inflammation.
复制标题
DOI：
10.1097/cji.0b013e3182943549
复制
发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Hellstrom KE
中科院分区：
文献类型：
--
作者：
Dai M;Wei H;Yip YY;Feng Q;He K;Popov V;Hellstrom I;Hellstrom KE
在肿瘤开始后7-15天，用针对CD 137 +PD-1+ CTLA 4的单克隆抗体（mAb）注射具有腹膜内ID 8卵巢癌或皮下SW 1黑素瘤的小鼠。具有ID 8肿瘤的小鼠的存活率增加了两倍，并且>40%的具有SW 1肿瘤的小鼠在后期治疗后保持健康>150天，并且可能被治愈。治疗效果与具有记忆和抗原特异性的全身免疫应答相关，需要CD 4+细胞，并在较小程度上涉及CD 8+细胞和NK细胞。3 mAb联合治疗显著降低了肿瘤部位的CD 19+细胞，增加了产生IFNγ和TNFα的CD 4+和CD 8 + T细胞以及成熟的CD 86 + DC，并增加了效应CD 4+和CD 8 + T细胞与CD 4 + Foxp 3+调节性T细胞和CD 11b +Gr-1+骨髓抑制细胞的比例。这与肿瘤微环境从免疫抑制性Th 2型向免疫刺激性Th 1型的转变相一致，并得到PCR数据的进一步支持。在SW 1模型中，将抗CD 19 mAb添加至3种mAb组合进一步增加了治疗功效。来自正在进行的实验的数据显示，肿瘤内注射针对CD 137 +PD-1+ CLA 4 + CD 19的mAb的组合也可以在TC 1癌和B16黑色素瘤模型中诱导完全消退并显著延长存活，这表明该方法具有普遍有效性。
Mice with intraperitoneal ID8 ovarian carcinoma or subcutaneous SW1 melanoma were injected with monoclonal antibodies (mAbs) to CD137+PD-1+CTLA4 7-15 days following tumor initiation. Survival of mice with ID8 tumors tripled and >40% of mice with SW1 tumors remain healthy >150 days after later treatment and are probably cured. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity and required CD4+ cells and involved CD8+ cells and NK cells to a less extent. The 3 mAb combination significantly decreased CD19+ cells at tumor sites, increased IFNγ and TNFα producing CD4+ and CD8+ T cells and mature CD86+ DC, and it increased the ratios of effector CD4+ and CD8+ T cells to CD4+Foxp3+ regulatory T cells and to CD11b+Gr-1+ myeloid suppressor cells. This is consistent with shifting the tumor microenvironment from an immunosuppressive Th2 to an immunostimulatory Th1 type and is further supported by PCR data. Adding an anti-CD19 mAb to the 3 mAb combination in the SW1 model further increased therapeutic efficacy. Data from ongoing experiments show that intratumoral injection of a combination of mAbs to CD137+PD-1+CLA4+CD19 can induce complete regression and dramatically prolong survival also in the TC1 carcinoma and B16 melanoma models, suggesting that the approach has general validity.