Poor prognosis is associated with melanoma due to immunosuppression profiles, suggesting that immune alterations have an important role in the occurrence, growth, and metastasis of melanoma. Here, we found that PCC0208018, a small-molecule compound, enhanced T cell proliferation and activation to release interferon gamma (IFN-γ) and interleukin-2 (IL-2) without blocking the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) binding and did not directly affect tumor cell viability in vitro. Furthermore, PCC0208018 increased the phosphorylation of protein kinase B (PKB/AKT) as well as extracellular regulated protein kinases (ERK) in human peripheral blood mononuclear cells (PBMCs) in vitro. The secretion of cytokines induced by PCC0208018 was significantly suppressed by the PI3K inhibitor GDC-0941. In B16-F10 melanoma-harboring mice, PCC0208018 significantly inhibited tumor growth as well as increasing CD3+, CD3+CD4+, and CD3+CD8+ T cell abundance in tumors without affecting PD-L1 expression. This study showed that PCC0208018 potentially increased PBMCs proliferation and function by activating the phosphatidylinositol 3 kinase (PI3K)/AKT and mitogen-activated protein kinase (MEK)/ERK pathways to exert antitumor effects.

中文翻译：

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PCC0208018通过激活效应T细胞发挥抗肿瘤作用。

由于免疫抑制特征，不良的预后与黑色素瘤有关，这表明免疫改变在黑色素瘤的发生，生长和转移中具有重要作用。在这里，我们发现PCC0208018是一种小分子化合物，可增强T细胞增殖和激活，从而释放干扰素γ（IFN-γ）和白介素2（IL-2），而不会阻止程序性细胞死亡1（PD-1）/程序性细胞死亡配体1（PD-L1）绑定，并没有直接影响体外肿瘤细胞的生存能力。此外，PCC0208018在体外增加了人外周血单个核细胞（PBMC）中蛋白激酶B（PKB / AKT）的磷酸化以及细胞外调节蛋白激酶（ERK）的磷酸化。PIC3K抑制剂GDC-0941显着抑制了PCC0208018诱导的细胞因子的分泌。在携带B16-F10黑色素瘤的小鼠中，PCC0208018显着抑制肿瘤生长，并增加肿瘤中CD3 +，CD3 + CD4 +和CD3 + CD8 + T细胞的丰度，而不会影响PD-L1的表达。这项研究表明，PCC0208018通过激活磷脂酰肌醇3激酶（PI3K）/ AKT和有丝分裂原激活的蛋白激酶（MEK）/ ERK途径来发挥抗肿瘤作用，从而可能增加PBMC的增殖和功能。