腫瘤逃避免疫攻擊造成癌症的進展和癌症免疫療法的失敗。癌細胞藉由發展出不同的機制來逃避免疫監視，例如通過分泌免疫抑制分子或募集免疫抑制細胞。骨髓來源的抑制細胞和腫瘤相關巨噬細胞都屬於免疫抑制性髓細胞，並且在腫瘤微環境中含量豐富。這些免疫抑制性髓細胞表達並分泌精胺酸酶1，將精胺酸分解為鳥胺酸，進而抑制了T細胞和NK細胞的增生與活化。此外，許多研究指出精胺酸酶1在不同的癌症中有高表達的現象。因此，抑制精胺酸酶1可以成為癌症治療的一種策略。L-正纈胺酸是一種非競爭性精胺酸酶抑製劑；然而，關於其在癌症治療上的應用仍是有限的。因此，我們想要研究L-正纈胺酸是否可以引起抗腫瘤免疫反應。在本研究中，我們發現濃度低於0.5 mg/mL的L-正纈胺酸在B16F10黑色素瘤細胞系中沒有細胞毒性，但在B16F10黑色素瘤動物模型中卻抑制了腫瘤的生長。組織免疫染色的結果表示L-正纈胺酸增加了浸潤腫瘤中的CD8+ T細胞。而流式細胞術分析顯示，在L-正纈胺酸治療後，脾臟中CD8+ T細胞和NK細胞增加，而淋巴結中僅NK細胞增加。此結果說明了L-正纈胺酸可能通過恢復T細胞的生長來抑制腫瘤的進展。此外，L-正纈胺酸與化療藥物順鉑聯合治療可增強原有的抗腫瘤反應。最後，我們進行RNA定序及生物資訊分析以探討L-正纈胺酸是否能藉由調控腫瘤細胞的基因表達而去治療癌症。結果顯示L-正纈胺酸參與調控免疫、神經及細胞分化的路徑。本研究發現L-正纈胺酸作為癌症藥物治療的可能性，並提供其潛在調控的機制。

Tumor immune escape is associated with tumor progression and the failure of cancer immunotherapy. Cancer cells develop different mechanisms to evade immune surveillance, such as by secreting immunosuppressive molecules or recruiting immunosuppressive cells. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) belong to immunosuppressive myeloid cells and are abundant in the tumor microenvironment. These immunosuppressive myeloid cells express and secret the enzyme arginase 1 (ARG1) which catabolizes arginine to ornithine and inhibits T cell proliferation through arginine degradation. Moreover, it has been reported that ARG1 is highly expressed in many cancers. Thus, the inhibition of ARG1 can be a therapeutic strategy for cancer treatment. L-norvaline is a non-competitive arginase inhibitor. However, there is limited understanding about L-norvaline on cancer treatment. Therefore, we aimed to investigate whether L-norvaline could exert an antitumor immune response. In this study, we found that L-norvaline showed no cytotoxic effect at concentration lower than 0.5 mg/mL in B16F10 melanoma cell line but reduced tumor growth in B16F10 tumor-bearing mice. Immunohistochemical staining showed that L-norvaline increased the tumor-infiltrating CD8+ T cells. The flow cytometric analysis revealed that L-norvaline treatment increased CD8+ T cells and NK cells in the spleen while only NK cells were increased in the lymph nodes. It suggested that L-norvaline might inhibit tumor progression by recovering T cells growth. In addition, combined treatment with L-norvaline and the chemotherapeutic drug cisplatin enhanced the antitumor response. Finally, we performed RNA sequencing and pathway enrichment analysis to investigate whether L-norvaline induced antitumor response by regulating gene expression of tumor cells. The results showed that L-norvaline was involved in regulating immune, nerve and cell differentiation pathways. This study implied the possibility of L-norvaline as a cancer therapeutic and provided its underlying mechanisms.

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