一氧化氮釋放藥物普遍用於治療心血管疾病； 然而，它們對腫瘤當中的免疫系統之影響尚不清楚。 因此，本研究探討了一氧化氮供體於免疫健全小鼠之腫瘤發展的影響。我們在腫瘤攜帶小鼠模型中探討三種不同的一氧化氮釋放化合物（SNAP、SNP 和 ISMN）對腫瘤生長的影響。本實驗使用三種小鼠腫瘤模型：B16F1黑色素瘤和 LL2 肺癌攜帶C57BL/6小鼠，以及CT26 大腸癌攜帶BALB/c 小鼠，以及LL2 肺癌 攜帶NOD/SCID 小鼠。 經由一氧化氮治療後，我們使用流式細胞儀以及細胞激素陣列分析小鼠脾臟淋巴細胞以及其分泌之細胞激素，也使用流式細胞儀以及單細胞RNA測序分析腫瘤微環境當中的浸潤淋巴細胞。我們發現外源性低濃度一氧化氮供體抑制腫瘤生長於兩種免疫健全之腫瘤攜帶小鼠動物模式，但對於NOD-SCID免疫缺陷小鼠之腫瘤生長沒有抑制效果。低濃度一氧化氮供體增加脾臟之細胞激素IFN-γ 以及TNF-α表現，但減少細胞激素IL-6以及IL-10表現，意味著改變了Th2細胞群的平衡。在單細胞定序分析中我們發現低濃度一氧化氮供體增加CD8+ T細胞及其代表活化之基因。而在流式細胞儀的分析當中也再次確認增加腫瘤浸潤之毒殺型CD8+ T細胞以及成熟樹突狀細胞。此外，低濃度一氧化氮供體所造成之抗腫瘤效果在CD8+ T細胞去除後則被破壞，證明了CD8+ T細胞於此反應的重要性。此外，我們也發現低濃度一氧化氮治療引起的抑制腫瘤效果與減少有促腫瘤生長特性之巨噬細胞 (TAM1-0) 以及增加同時表現Arginase 1基因和抗腫瘤生長之特異性基因的巨噬細胞 (TAM1-1)有關。而該巨噬細胞群體 (TAM1-1) 也利用流式細胞儀方式再次證明其群落在治療後有增加。最後，我們也發現合併治療低濃度一氧化氮供體以及抗癌藥物順鉑能夠造成疊加的抗腫瘤效果於免疫健全小鼠模式當中。此合併治療伴隨著更多表現自然殺手細胞之基因的浸潤於腫瘤微環境當中。綜合以上結論我們發現外源性低濃度之一氧化氮供體在動物體內透過調控T細胞以及巨噬細胞來抑制腫瘤生長。而在其中CD8+ T細胞對於抗腫瘤效果是必須的。此外，低濃度一氧化氮供體也許在未來可以合併化學治療藥物於腫瘤治療當中。

Nitric oxide-releasing drugs are commonly used to treat cardiovascular diseases, but their effects on the immune system in the context of cancer are not well understood. This study investigated the impact of nitric oxide donors on tumor progression in immunocompetent mice. We used three different nitric oxide-releasing compounds (S-Nitroso-N-acetyl-DL-penicillamine; SNAP, Sodium nitroprusside; SNP, and Isosorbide-5-mononitrate; ISMN) and three different types of tumor-bearing mouse models: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After treatment with nitric oxide, we used cytokine arrays and flow cytometry to analyze splenic cytokines and lymphocytes, and also used flow cytometry and single-cell RNA sequencing to study the tumor-infiltrating lymphocytes in the tumor microenvironment (TME). We found that the low doses of the exogenous nitric oxide donors inhibit tumor growth in two of the immunocompetent mouse models, but not in the immunodeficient NOD/SCID mice. The low-dose nitric oxide donors increased the levels of IFN-γ and TNF-α in the spleen, but decreased the levels of IL-6 and IL-10, suggesting a shift in the balance of Th2 responses. We also found that the low-dose nitric oxide donors increased the number of CD8+ T cells with activated gene signatures, as indicated by single-cell RNA sequencing, and flow cytometry analysis confirmed an increase in infiltrating cytotoxic CD8+ T cells and DCs. Depletion of CD8+ T cells completely abolished the antitumor effect of the low-dose nitric oxide donors, indicating that these T cells are essential for the observed effects. We also observed a decrease in a subtype of pro-tumor macrophages and an increase in a subset of Arginase 1-positive macrophages expressing antitumor gene signatures. This was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin had an additive cancer therapeutic effect in two of the immunocompetent animal models, and this was accompanied by an increase in cells expressing the gene signature of natural killer (NK) cells. In summary, low concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages, and CD8+ T cells are essential for this effect. In addition, the combination of low-dose nitric oxide donors and chemotherapeutic drugs may have potential as a cancer therapy in the future.

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