Inflammation driven by tumor-specific Th1 cells protects against B-cell cancer. Mus musculus

The immune system can both promote and suppress cancer. Chronic inflammation and proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are considered tumor-promoting. In contrast, the exact nature of protective antitumor immunity remains obscure. In this study, we have quantified locally secreted cytokines during primary immune responses against myeloma and B-cell lymphoma in mice. Strikingly, successful cancer immunosurveillance mediated by tumor-specific CD4+ T cells was consistently associated with elevated local levels of both proinflammatory (IL-1aplha, IL-1beta, and IL-6) and T helper 1 (Th1)-associated cytokines (interferon-alpha, IL-2, IL-12). Cancer eradication was achieved by a collaboration between tumor-specific Th1 cells and tumor-infiltrating, antigen-presenting macrophages. Th1 cells induced secretion of IL-1? and IL-6 by macrophages. Th1-derived interferon-? was shown to render macrophages directly cytotoxic to cancer cells, and to induce macrophages to secrete the angiostatic chemokines CXCL9/MIG and CXCL10/IP-10. Thus, inflammation, when driven by tumor-specific Th1 cells, may prevent rather than promote cancer. Overall design: Tumoricidal macrophages were isolated from Idiotype-specific TCR-transgenic SCID mice injected with MOPC315-containing Matrigel. Control macrophages were obtained from TCR-transgenic SCID mice injected with Matrigel containing antigen-loss MOPC315.免疫系统既可促进癌症发生，亦可抑制癌症发展。慢性炎症以及白细胞介素（interleukin, IL）-1、IL-6等促炎细胞因子，被认为具有促瘤活性。与之相对，介导保护性抗肿瘤免疫的核心机制仍未明确。本研究针对小鼠体内针对骨髓瘤与B细胞淋巴瘤的初次免疫应答过程中局部分泌的细胞因子开展了定量检测。值得注意的是，由肿瘤特异性CD4+ T细胞介导的有效肿瘤免疫监视，始终与促炎细胞因子（IL-1α、IL-1β及IL-6）与T辅助1型（T helper 1, Th1）相关细胞因子（干扰素-α、IL-2、IL-12）的局部水平升高密切相关。肿瘤的清除依赖于肿瘤特异性Th1细胞与肿瘤浸润性抗原呈递巨噬细胞的协同作用。Th1细胞可诱导巨噬细胞分泌IL-1β与IL-6。研究证实，Th1细胞来源的干扰素-α可使巨噬细胞直接对癌细胞产生细胞毒性，并诱导巨噬细胞分泌血管生成抑制性趋化因子CXCL9/MIG与CXCL10/IP-10。由此可见，由肿瘤特异性Th1细胞驱动的炎症反应，反而可预防癌症发生，而非促进其发展。总体实验设计：从注射了含MOPC315的基质胶（Matrigel）的独特型特异性TCR转基因SCID小鼠中分离得到杀瘤巨噬细胞；对照组巨噬细胞则取自注射了缺失抗原的MOPC315基质胶的TCR转基因SCID小鼠。