给免疫治疗“减毒”“增效”的药物（四）--己酮可可碱

一、抑制c-rel，既能抑制treg，又能抑制MDSC，从而增强ici的疗效
1、“Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. ” （《NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer》）
2、“Here we show that c-Rel, a member of the nuclear factor (NF)-B family, specified the generation of myeloid-derived suppressor cells (MDSCs) by selectively turning on pro-tumoral genes while switching off anti-tumoral genes through a c-Rel enhanceosome. c-Rel deficiency in myeloid cells markedly inhibited cancer growth in mice, and pharmaceutical inhibition of c-Rel had the same effect. Combination therapy that blocked both c-Rel and the lymphoid checkpoint protein PD1 was more effective in treating cancer than blocking either alone.” （《c-Rel Is a Myeloid Checkpoint for Cancer Immunotherapy》）
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二、己酮可可碱是 c-rel抑制剂
4 }* G3 L3 v+ j“Pentoxifylline (PTXF) is a xanthine derivative that has been approved by FDA for clinical use for a wide variety of clinical conditions over the past 30 years. PTXF has been proposed to act through multiple targets in vivo, including as a potent inhibitor of c-Rel expression and activation in T cells (Neo et al., 2014; Wang et al., 1997). In our hands, treatment of Tregs with PTXF led to a significant reduction of c-Rel protein, whereas levels of p65 were unaffected (Figure 3A).” （《NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer》）

三、减毒作用机制
“己酮可可碱是一种广泛用于改善血液流变性的非特异性磷酸二酯酶抑制剂，具有有益的抗炎特性，并能显著降低促炎细胞因子如白细胞介素(IL)-6、IL-1、肿瘤坏死因子-α、C-反应蛋白和其他免疫调节剂的血清水平。还发现它具有抗血栓形成作用”“Pentoxifylline, a non-specific phosphodiesterase inhibitor widely used to improve the rheological properties of blood, has beneficial anti-inflammatory properties and can significantly reduce the serum levels of pro-inflammatory cytokines such as interleukin (IL)-6, IL-1, tumour necrosis factor-alpha, C-reactive protein and other immunoregulators. It has also been found to exert anti-thrombotic actions.” （《Potential usefulness of pentoxifylline, a non-specific phosphodiesterase inhibitor with anti-inflammatory, anti-thrombotic, antioxidant, and anti-fibrogenic properties, in the treatment of SARS-CoV-2》）