High-risk prostate cancer (PCa) is a leading cause in cancer death and can elicit significant morbidity and mortality. Currently, the salvage of local disease recurrence after radiation therapy (RT) is a major clinical problem. Immune checkpoint inhibitors (ICIs), which enhance immune activation, have demonstrated clinical therapeutic promise in combination with ionizing radiation (IR) in certain advanced cancers. We generated the TRAMP-C2 HF radiorecurrent syngeneic mouse model to evaluate the therapeutic efficacy of ICIs in combination with RT. The administration of anti-PDL1 and/or anti-CTLA4 did not achieve a significant tumor growth delay compared to the control. The combination of IR and anti-PDL1 did not yield additional a growth delay compared to IR and the isotype control. Strikingly, a significant tumor growth delay and complete cure in one-third of the mice were seen with the combination of IR and anti-CTLA4. Immune cells in tumor-draining lymph nodes and tumor-infiltrating lymphocytes from mice treated with IR and anti-CTLA4 demonstrated an upregulation of genes in T-cell functions and enrichment in both CD4+ and CD8+ T-cell populations compared to mice given IR and the isotype control. Taken together, these results indicate enhancement of T-cell response in radiorecurrent PCa by IR and anti-CTLA4.
高危前列腺癌是导致癌症死亡的主要原因之一，可引发显著的发病率和死亡率。目前，放射治疗后局部疾病复发的挽救治疗是临床面临的主要难题。免疫检查点抑制剂通过增强免疫激活作用，已在部分晚期癌症中与电离辐射联合应用展现出临床治疗潜力。本研究构建了TRAMP-C2 HF放射后复发同系小鼠模型，以评估免疫检查点抑制剂联合放射治疗的疗效。与对照组相比，抗PDL1和/或抗CTLA4单药治疗未能实现显著的肿瘤生长延迟。放射治疗联合抗PDL1方案相较于放射治疗联合同型对照方案，亦未产生额外的生长延迟效应。值得注意的是，放射治疗联合抗CTLA4方案不仅实现了显著的肿瘤生长延迟，更使三分之一的小鼠获得完全治愈。与接受放射治疗联合同型对照的小鼠相比，放射治疗联合抗CTLA4治疗组小鼠的肿瘤引流淋巴结免疫细胞及肿瘤浸润淋巴细胞中，T细胞功能相关基因表达上调，且CD4+和CD8+T细胞群体均呈现富集现象。综上所述，这些结果表明放射治疗联合抗CTLA4能够增强放射后复发前列腺癌的T细胞免疫应答。
肿瘤(癌症)患者之家