PDF(Pubmed)
Abstract：
Bacillus Calmette-Guérin (BCG) is the first line treatment for bladder cancer and it is also proposed for melanoma immunotherapy. BCG modulates the tumor microenvironment (TME) inducing an antitumor effective response, but the immune mechanisms involved still poorly understood. The immune profile of B16-F10 murine melanoma cells was assessed by infecting these cells with BCG or stimulating them with agonists for different innate immune pathways such as TLRs, inflammasome, cGAS-STING and type I IFN. B16-F10 did not respond to any of those stimuli, except for type I IFN agonists, contrasting with bone marrow-derived macrophages (BMDMs) that showed high production of proinflammatory cytokines. Additionally, we confirmed that BCG is able to infect B16-F10, which in turn can activate macrophages and spleen cells from mice in co-culture experiments. Furthermore, we established a subcutaneous B16-F10 melanoma model for intratumoral BCG treatment and compared wild type mice to TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, MyD88-/-deficient animals. These results in vivo demonstrate that MyD88 signaling is important for BCG immunotherapy to control melanoma in mice. Also, BCG fails to induce cytokine production in the co-culture experiments using B16-F10 and BMDMs or spleen cells derived from MyD88-/- compared to wild-type (WT) animals. Immunotherapy with BCG was not able to induce the recruitment of inflammatory cells in the TME from MyD88-/- mice, impairing tumor control and IFN-γ production by T cells. In conclusion, MyD88 impacts on both innate and adaptive responses to BCG leading to an efficient antitumor response against melanoma.
摘要：
卡介苗（BCG）是膀胱癌的一线治疗方法，也被提议用于黑色素瘤免疫治疗。卡介苗调节肿瘤微环境（TME）诱导抗肿瘤有效反应，但涉及的免疫机制仍然知之甚少。B16-F10鼠黑色素瘤细胞的免疫谱是通过用BCG感染这些细胞或用不同的先天性免疫途径如TLR的激动剂刺激它们来评估的。炎性体,cGAS-STING和I型IFN。B16-F10对这些刺激没有反应，除了I型IFN激动剂，与骨髓来源的巨噬细胞（BMDMs）相反，后者显示出高产量的促炎细胞因子。此外,我们证实，BCG能够感染B16-F10，这反过来可以激活小鼠的巨噬细胞和脾细胞共培养实验。此外，我们建立了皮下B16-F10黑色素瘤模型，用于肿瘤内BCG治疗，并将野生型小鼠与TLR2-/-，TLR3-/-,TLR4-/-,TLR7-/-,TLR3/7/9-/-,caspase1-/-,caspase11-/-,IL-1R-/-,cGAS-/-,STING-/-,IFNAR-/-,MyD88-/-缺陷动物。这些体内结果证明MyD88信号传导对于BCG免疫疗法控制小鼠中的黑素瘤是重要的。此外，与野生型(WT)动物相比,在使用B16-F10和BMDM或源自MyD88-/-的脾细胞的共培养实验中,BCG未能诱导细胞因子产生。BCG的免疫治疗不能诱导MyD88-/-小鼠TME中炎症细胞的募集，损害肿瘤控制和T细胞产生IFN-γ。总之,MyD88影响对BCG的先天和适应性反应,导致针对黑色素瘤的有效抗肿瘤反应。
