Department of Urology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Int J Mol Sci. 2021 Jan 7;22(2):535. doi: 10.3390/ijms22020535.
The therapeutic benefit of immune checkpoint inhibitor monotherapy is limited to a subset of patients in urothelial carcinoma (UC). Previous studies showed the immunogenicity of cisplatin and irradiation. Here, we investigated whether chemoradiotherapy (CRT), a combination of cisplatin and irradiation, could improve the efficacy of postirradiation anti-programmed cell death 1 (PD-1) treatment in UC. In our advanced UC patient cohort, patients with CRT showed a significantly better objective response rate (75%/22%) and overall survival (88%/30% at 12 months) following later pembrolizumab therapy compared to those without. Then, we created syngeneic UC mouse models by inoculating MB49 cells s.c. in C57BL/6J mice to examine the potential of CRT to enhance antitumor immunity in conjunction with postirradiation anti-PD-1 treatment. Nonirradiated tumors of the mice treated with CRT/postirradiation anti-PD-1 treatment had a significantly slower growth rate and a significantly higher expression of cytotoxic T cells compared to those of the mice treated with anti-PD-1 treatment alone. The mice treated with CRT/postirradiation anti-PD-1 treatment showed the best survival. Mechanistically, CRT provoked strong direct cytotoxicity and increased expressions of immunogenic cell death markers in MB49 cells. Therefore, the combination of cisplatin and irradiation induces immunogenic cell death and potentiates postirradiation anti-PD-1 treatment efficacy in UC.
免疫检查点抑制剂单药治疗的疗效仅限于一部分尿路上皮癌（UC）患者。先前的研究表明顺铂和放疗具有免疫原性。在这里，我们研究了顺铂和放疗的联合化疗（CRT）是否可以提高 UC 患者放疗后抗程序性细胞死亡蛋白 1（PD-1）治疗的疗效。在我们的晚期 UC 患者队列中，与未接受 CRT 的患者相比，接受 CRT 后再接受 pembrolizumab 治疗的患者客观缓解率（75%/22%）和总生存率（12 个月时为 88%/30%）显著提高。然后，我们通过将 MB49 细胞皮下接种于 C57BL/6J 小鼠中创建了同源 UC 小鼠模型，以检查 CRT 与放疗后抗 PD-1 治疗联合使用增强抗肿瘤免疫的潜力。与单独接受抗 PD-1 治疗的小鼠相比，接受 CRT/放疗后抗 PD-1 治疗的小鼠未照射的肿瘤生长速度明显较慢，细胞毒性 T 细胞的表达明显较高。接受 CRT/放疗后抗 PD-1 治疗的小鼠的存活率最高。从机制上讲，CRT 引发了 MB49 细胞强烈的直接细胞毒性和免疫原性细胞死亡标志物的表达增加。因此，顺铂和放疗的联合使用诱导了免疫原性细胞死亡，并增强了 UC 患者放疗后抗 PD-1 治疗的疗效。
