Zhong RuiKun, Li Hongying, Messer Karen, Lane Thomas A, Zhou Jiehua, Ball Edward D
Division of Blood and Marrow Transplantation, Departments of Medicine, Pathology and the Moores UCSD Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA, 92093-0960, USA.
Cancer Immunol Immunother. 2015 Jun;64(6):737-44. doi: 10.1007/s00262-015-1680-x. Epub 2015 Mar 21.
This study investigated whether TNF-α, Toll-like receptors (TLRs) 7/8 agonist resiquimod (R848), the TLR4 agonist lipopolysaccharide (LPS) and their combinations can enhance autologous AML-reactive T cell generation in an in vitro culture. AML peripheral blood or bone marrow mononuclear cells were cultured in medium supplemented with GM-CSF/IL-4 to induce dendritic cell (DC) differentiation of AML blasts (AML-DC). The impact of TNF-α, LPS, R848 and their combinations on AML-DC cultures was analyzed. Significantly enhanced CD80, CD40, CD83, CD54, HLA-DR and CD86 expression of AML cells was observed by addition of TNF-α, LPS, R848 alone or combinations. Induced CD80 expression of AML cells was significantly higher through the combination of TNF-α, LPS and R848 (T + L + R) than that by T alone. CTL induced from T + L + R, T + R, T + L, L + R and R, but not T, L alone stimulated cultures showed significantly higher IFN-γ release than the medium control in response to autologous AML cells. IFN-γ release by T + L + R was significantly higher than T or L alone, and T + R was significantly higher than T alone. CTL generated from T + L + R, T + L, T + R, L + R and L alone exerted significantly higher AML cell killing than medium control. AML cell killing by T + L + R and T + R was significantly higher than T or R alone. These results indicate that the combination of T + L + R induces a significantly enhanced antigen presentation effect of AML-DC. We speculate that the complementary effects of reagent combinations may better address the heterogeneity of responses to any single agent in AML cells from different patients.
本研究调查了肿瘤坏死因子-α（TNF-α）、Toll样受体（TLR）7/8激动剂瑞喹莫德（R848）、TLR4激动剂脂多糖（LPS）及其组合是否能在体外培养中增强自体抗急性髓系白血病（AML）反应性T细胞的生成。将AML外周血或骨髓单个核细胞在补充有粒细胞-巨噬细胞集落刺激因子（GM-CSF）/白细胞介素-4（IL-4）的培养基中培养，以诱导AML原始细胞分化为树突状细胞（AML-DC）。分析了TNF-α、LPS、R848及其组合对AML-DC培养物的影响。单独添加TNF-α、LPS、R848或其组合后，观察到AML细胞的CD80、CD40、CD83、CD54、人类白细胞抗原-DR（HLA-DR）和CD86表达显著增强。通过TNF-α、LPS和R848（T+L+R）组合诱导的AML细胞CD80表达显著高于单独使用T诱导的表达。从T+L+R、T+R、T+L、L+R和R诱导产生的细胞毒性T淋巴细胞（CTL），但不是单独的T、L刺激培养物，在对自体AML细胞的反应中显示出比培养基对照显著更高的γ干扰素（IFN-γ）释放。T+L+R释放的IFN-γ显著高于单独的T或L，T+R显著高于单独的T。从T+L+R、T+L、T+R、L+R和单独的L产生的CTL对AML细胞的杀伤作用显著高于培养基对照。T+L+R和T+R对AML细胞的杀伤作用显著高于单独的T或R。这些结果表明，T+L+R组合可显著增强AML-DC的抗原呈递效应。我们推测，试剂组合的互补效应可能更好地应对来自不同患者的AML细胞对任何单一试剂反应的异质性。
