Chen S, Zhang S, Fan W, Sun W, Liu B, Liu J, Guo Y
Department of Urology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233040, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2024 Feb 20;44(2):210-216. doi: 10.12122/j.issn.1673-4254.2024.02.02.
To assess the efficacy of pirfenidone combined with PD-L1 inhibitor for treatment of bladder cancer in a mouse model and its effect on tumor immune microenvironment modulation.
Forty C57BL/6 mouse models bearing ectopic human bladder cancer xenografts were randomized into control group, PD-L1 inhibitor group, pirfenidone group and combined treatment group (=10). After successful modeling, PD-L1 inhibitor treatment was administered via intraperitoneal injection at 12.5 mg/kg every 3 days, and oral pirfenidone (500 mg/kg) was given on a daily basis. The survival rate of the mice and tumor growth rate were compared among the 4 groups. The expressions of CD3, CD8, CD45, E-cadherin and N-cadherin in the tumor tissues were detected with immunohistochemistry after the 21-day treatment, and bone marrow-derived suppressor cells (MDSCs) were observed with immunofluorescence staining; serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN), creatinine (CRE) and lactate dehydrogenase (LDH-L) were analyzed using an automated biochemical analyzer.
Treatment with PD-L1 inhibitor and pirfenidone alone both significantly decreased tumor growth rate and tumor volume at 21 days ( < 0.05), but the combined treatment produced an obviously stronger inhibitory effect ( < 0.05). PD-L1 inhibitor and pirfenidone alone significantly increased E- cadherin expression and decreased N-cadherin expression in the tumor tissue ( < 0.05). The two treatments both significantly increased the percentage of CD3, CD8 and CD45 T cells and decreased the percentage of Ly-6GCD11bMDSCs in the tumor tissue, and these changes were more obvious in the combined treatment group ( < 0.05). No significant differences were found in serum ALT, AST, BUN, CRE or LDH-L levels among the 4 groups (>0.05).
Combined treatment with pirfenidone and PD-L1 inhibitor significantly inhibits the progression of bladder cancer in mice possibly by regulating tumor immune microenvironment and inhibiting epithelial-mesenchymal transition of the tumor cells.
在小鼠模型中评估吡非尼酮联合PD-L1抑制剂治疗膀胱癌的疗效及其对肿瘤免疫微环境调节的影响。
将40只携带人膀胱癌异种移植瘤的C57BL/6小鼠模型随机分为对照组、PD-L1抑制剂组、吡非尼酮组和联合治疗组（每组n = 10）。建模成功后，每3天通过腹腔注射给予PD-L1抑制剂，剂量为12.5 mg/kg，每日口服吡非尼酮（500 mg/kg）。比较4组小鼠的生存率和肿瘤生长率。治疗21天后，用免疫组织化学法检测肿瘤组织中CD3、CD8、CD45、E-钙黏蛋白和N-钙黏蛋白的表达，并用免疫荧光染色观察骨髓来源的抑制细胞（MDSCs）；使用自动生化分析仪分析血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、尿素氮（BUN）、肌酐（CRE）和乳酸脱氢酶（LDH-L）水平。
单独使用PD-L1抑制剂和吡非尼酮治疗均显著降低了21天时的肿瘤生长率和肿瘤体积（P < 0.05），但联合治疗产生了明显更强的抑制作用（P < 0.05）。单独使用PD-L1抑制剂和吡非尼酮均显著增加了肿瘤组织中E-钙黏蛋白的表达并降低了N-钙黏蛋白的表达（P < 0.05）。两种治疗均显著增加了肿瘤组织中CD3、CD8和CD45 T细胞的百分比，并降低了Ly-6G⁺CD11b⁺MDSCs的百分比，且这些变化在联合治疗组中更明显（P < 0.05）。4组之间血清ALT、AST、BUN、CRE或LDH-L水平无显著差异（P > 0.05）。
吡非尼酮与PD-L1抑制剂联合治疗可能通过调节肿瘤免疫微环境和抑制肿瘤细胞的上皮-间质转化，显著抑制小鼠膀胱癌的进展。
