Analyzing immunomodulatory elements operating during antitumor vaccination in prostate cancer patients and murine models we identified IL-10-producing DC as a subset with poorer immunogenicity and clinical efficacy. Inhibitory TAM receptors MER and AXL were upregulated on murine IL-10⁺ DC. Thus, we analyzed conditions inducing these molecules and the potential benefit of their blockade during vaccination. MER and AXL upregulation was more efficiently induced by a vaccine containing Imiquimod than by a poly(I:C)-containing vaccine. Interestingly, MER expression was found on monocyte-derived DC, and was dependent on IL-10. TAM blockade improved Imiquimod-induced DC activation in vitro and in vivo, resulting in increased vaccine-induced T-cell responses, which were further reinforced by concomitant IL-10 inhibition. In different tumor models, a triple therapy (including vaccination, TAM inhibition and IL-10 blockade) provided the strongest therapeutic effect, associated with enhanced T-cell immunity and enhanced CD8⁺ T cell tumor infiltration. Finally, MER levels in DC used for vaccination in cancer patients correlated with IL-10 expression, showing an inverse association with vaccine-induced clinical response. These results suggest that TAM receptors upregulated during vaccination may constitute an additional target in combinatorial therapeutic vaccination strategies.

分析在前列腺癌患者和小鼠模型中进行抗肿瘤疫苗接种期间起作用的免疫调节元件，我们将产生 IL-10 的 DC 确定为具有较差免疫原性和临床疗效的子集。抑制性 TAM 受体 MER 和 AXL 在小鼠 IL-10 ^{+上被上调}直流。因此，我们分析了诱导这些分子的条件以及在疫苗接种期间阻断它们的潜在益处。含有咪喹莫特的疫苗比含有聚 (I:C) 的疫苗更有效地诱导 MER 和 AXL 上调。有趣的是，在单核细胞衍生的 DC 上发现了 MER 表达，并且依赖于 IL-10。TAM 阻断在体外和体内改善了咪喹莫特诱导的 DC 活化，导致疫苗诱导的 T 细胞反应增加，伴随的 IL-10 抑制进一步加强了这种反应。在不同的肿瘤模型中，三联疗法（包括疫苗接种、TAM 抑制和 IL-10 阻断）提供了最强的治疗效果，与增强的 T 细胞免疫和增强的 CD8 ^+相关T细胞肿瘤浸润。最后，用于癌症患者疫苗接种的 DC 中的 MER 水平与 IL-10 表达相关，与疫苗诱导的临床反应呈负相关。这些结果表明，在疫苗接种期间上调的 TAM 受体可能构成组合治疗性疫苗接种策略中的额外目标。