The connection of innate and adaptive anti-cancer immunity

涉及CD8+ T细胞的免疫记忆是适应性抗原（Ag）特异性免疫反应的标志，是保护性免疫的重要组成部分。设计增强长期T细胞记忆的方法在很大程度上可以强化疫苗，增强宿主对传染病的保护，或许还可以增强癌症免疫治疗。对ag特异性t细胞反应中涉及的细胞程序的更好理解导致了针对记忆t细胞反应的大小和质量的新方法。我们已经证明，来自流感病毒NP68核蛋白的TCR （T细胞受体）转基因小鼠的T细胞在体外暴露于同源肽时表现出ag特异性T细胞反应的不同阶段——启动、扩张、收缩和记忆。Saracatinib是Src家族激酶的特异性抑制剂，在扩张期或收缩期低剂量给药，增加CD62Lhigh/CD44high中枢记忆CD8+ T细胞和ifn - γ的产生，但在启动期添加时抑制免疫。saracatinib的这些作用并不伴随着Src家族激酶的预期下降，而是伴随着akt -哺乳动物雷帕霉素抑制靶点和/或通过另一途径介导。在使用痘病毒流感疫苗的小鼠中重现了saracatinib增加的中枢记忆细胞，从而强调了在记忆t细胞分化背景下抑制剂的剂量和时间的重要性。最后，疫苗加萨拉卡替尼治疗对肿瘤侵袭有更好的保护作用。低剂量saracatinib对CD8+ T细胞的免疫增强作用可能在与疫苗联合使用时提供更好的对病原体或癌症的保护。

Immunologic memory involving CD8+ T cells is a hallmark of an adaptive antigen (Ag)-specific immune response and constitutes a critical component of protective immunity. Designing approaches that enhance long-term T cell memory would, for the most part, fortify vaccines and enhance host protection against infectious diseases and, perhaps, cancer immunotherapy. A better understanding of the cellular programs involved in the Ag-specific T-cell response has led to new approaches that target the magnitude and quality of the memory T-cell response. We have shown that T cells from TCR (T-cell receptor) transgenic mice for the nucleoprotein of influenza virus NP68 exhibit the distinct phases - priming, expansion, contraction, and memory - of an Ag-specific T-cell response when exposed in vitro to the cognate peptide. Saracatinib, a specific inhibitor of Src family kinases, administered at low doses during the expansion or contraction phases, increased CD62Lhigh/CD44high central memory CD8+ T cells and IFN-gamma production but suppressed immunity when added during the priming phase. These effects by saracatinib were not accompanied by the expected decline of Src family kinases but were accompanied by Akt-mammalian target of rapamycin suppression and/or mediated via another pathway. Increased central memory cells by saracatinib were recapitulated in mice using a poxvirus-based influenza vaccine, thus underscoring the importance of dose and timing of the inhibitor in the context of memory T-cell differentiation. Finally, vaccine plus saracatinib treatment showed better protection against tumor challenge. The immune-potentiating effects on CD8+ T cells by a low dose of saracatinib might afford better protection from pathogens or cancer when combined with vaccine.