Data_Sheet_1_Adenosinergic Signaling Alters Natural Killer Cell Functional Responses.docx

Adenosine is a potent immunosuppressive purine metabolite contributing to the pathogenesis of solid tumors. Extracellular adenosine signals on tumor-infiltrating NK cells to inhibit their proliferation, maturation, and cytotoxic function. Cytokine priming imparts upon NK cells distinct activation statuses, which modulate NK anti-tumor immunity and responses to purinergic metabolism. Here, for the first time, we investigated human NK cell responses to adenosinergic signaling in the context of distinct cytokine priming programs. NK cells were shown to be hyper-responsive to adenosine when primed with IL-12 and IL-15 compared to IL-2, exhibiting enhanced IFN-γ expression from CD56bright and CD56dim subsets while modulating the expression of activation marker NKG2D. These responses resulted in signaling that was dependent on mTOR. Adenosine induced upregulation of transcriptional signatures for genes involved in immune responses while downregulating cellular metabolism and other protein synthesis functions that correlate to inhibited oxidative phosphorylation and glycolysis. Overall, our findings show that adenosine acts on specific cellular pathways rather than inducing a broad inhibition of NK cell functions. These responses are dependent on cytokine priming signatures and are important in designing therapeutic interventions that can reprogram NK cell immunometabolism for improved immunotherapies of solid tumors.

腺苷作为一种高效的免疫抑制嘌呤代谢产物，对实体肿瘤的发生发展起着重要作用。细胞外腺苷信号在肿瘤浸润性自然杀伤细胞上发挥作用，抑制其增殖、成熟及细胞毒性功能。细胞因子预激活赋予自然杀伤细胞不同的激活状态，进而调节自然杀伤细胞抗肿瘤免疫及对嘌呤代谢的反应。本研究首次探究了在特定细胞因子预激活程序下，人自然杀伤细胞对腺苷信号的响应。研究发现，与IL-2预激活相比，在IL-12和IL-15预激活下，自然杀伤细胞对腺苷表现出超敏感性，CD56bright和CD56dim亚群中IFN-γ表达增强，同时调节激活标志物NKG2D的表达。这些反应依赖于mTOR信号通路。腺苷诱导上调与免疫反应相关的基因转录特征，同时下调与抑制氧化磷酸化和糖酵解相关的细胞代谢及其他蛋白质合成功能。总体而言，我们的研究结果表明，腺苷作用于特定的细胞信号通路，而非引起自然杀伤细胞功能的广泛抑制。这些反应依赖于细胞因子预激活特征，对于设计能够重新编程自然杀伤细胞免疫代谢、以改善实体肿瘤免疫疗法的治疗干预措施具有重要意义。