IDDF2022-ABS-0247 YTHDF1-EZH2-il-6 axis fuels anti-PD-1 resistance in nash-HCC

Homologous-Magnetic Dual-Targeted Metal-Organic Framework to Improve the Anti-Hepatocellular Carcinoma Efficacy of PD-1 Inhibitor

“…This limited e cacy can be attributed to the presence of immunosuppressive factors in the tumour microenvironment, such as TGF-β1, IL-6 and IL-10, which suppress the activity of TILs. [51][52][53] TGF-β1 is a prototypical immunosuppressive factor known to induce TIL exhaustion and compromise the e cacy of anti-PD-1/PD-L1 therapies. [51][52][53][54] In addition, IL-6 and IL-10 also can contribute to the inhibition of the anti-tumour activity of TILs.…”

“…[51][52][53] TGF-β1 is a prototypical immunosuppressive factor known to induce TIL exhaustion and compromise the e cacy of anti-PD-1/PD-L1 therapies. [51][52][53][54] In addition, IL-6 and IL-10 also can contribute to the inhibition of the anti-tumour activity of TILs. [52,53,55,56] Immuno uorescence analysis was performed to evaluate the levels of TGF-β1, IL-6 and IL-10, in HCC tissues.…”

“…[51][52][53][54] In addition, IL-6 and IL-10 also can contribute to the inhibition of the anti-tumour activity of TILs. [52,53,55,56] Immuno uorescence analysis was performed to evaluate the levels of TGF-β1, IL-6 and IL-10, in HCC tissues. As shown in Figure . 7A and Figure . 7B, the combination group exhibited the least uorescent signals of TGF-β1, followed by the Hm@TSA/As-MOF group.…”

The role of RNA methylation in tumor immunity and its potential in immunotherapy

“…Additionally, YTHDF1 is implicated in inducing resistance to ICIs by promoting the degradation of MHC-I molecules; inhibiting YTHDF1 can transform immunologically "cold" tumors into "hot" ones, making them more amenable to therapy [60]. YTHDF1 also contributes to the dysfunction of cytotoxic CD8 + T cells by encouraging the accumulation of MDSCs through IL-6 secretion, presenting a novel target for ICB immunotherapy [338]. Furthermore, both methionine metabolites and YTHDF1 are known to enhance the translation of immune checkpoints such as PD-L1 and VISTA, suggesting that targeting these processes could be an innovative strategy for ICB [187].…”

The New Perspectives Journal of Medicine

“…www.npjmjournal.com (86) 4.2. m 6 A在肝癌免疫治疗中的作用 免疫治疗是通过诱导、增强或是抑制免疫应答来治疗 疾病。PD-1是众所周知的免疫抑制分子，可以通过抑制 T细胞活性来抑制免疫反应，促进肿瘤的免疫耐受。有研 究报道，甲基转移酶WTAP介导的m 6 A修饰通过与结合蛋 白IDF2BP3共同作用增强了外泌体circCCAR1的稳定性， 而circCCAR1被CD8+ T细胞吸收，并通过稳定PD-1蛋白 导致CD8+ T细胞功能障碍 (89) 。IDO1通过调节T细胞相关 免疫应答和促进免疫抑制的活化来负责肿瘤免疫逃逸， 而Abrine是一种IDO1抑制剂，与抗PD-1抗体对肝癌的 治疗具有协同作用 (90) 。在非酒精性脂肪性肝炎相关HCC (NASH-HCC)中YTHDF1高表达，同时通过EZH2-IL-6 信号传导促进NASH-HCC肿瘤发生，其招募并激活髓源 性抑制细胞(MDSCs)导致细胞毒性CD8 T细胞功能障 碍 (91) 。免疫检查点阻断(ICB)这种治疗方法已显示出抑 制复发和转移的潜力，有实验将ICB和热消融(TA)联 合起来对HCC进行治疗，将肿瘤相关抗原(TAAs)和去 甲基化酶FTO共同递送到肿瘤浸润树突状细胞(TIDC) 中，结果显示，可以改善效应T细胞的肿瘤浸润并产生免 疫记忆，与ICB治疗协同作用，抑制远处HCC生长和肺转 移 (92) (93) 。此外，沉默circRNA-SORE显著的提高了索拉非尼诱 导HCC凋亡的功效 (94) 。FZD10在肝脏干细胞中的激活是 由FZD10 mRNA的METTL3依赖性N 6 -甲基腺苷甲基化介 导的，而FZD10/β-连环蛋白/c-Jun/MEK/ERK信号通路决 定了肝癌细胞对仑伐替尼治疗的反应 (95) 。另一种甲基转 移酶KIAA1429通过介导m 6 A甲基化来促进索拉非尼耐药 的肝细胞癌侵袭、迁移和上皮间充质转化(EMT) (96) 。 总的来说，m 6…”