Kato Renpei, Jinnouchi Noriaki, Tuyukubo Takashi, Ikarashi Daiki, Matsuura Tomohiko, Maekawa Shigekatsu, Kato Yoichiro, Kanehira Mitsugu, Takata Ryo, Ishida Kazuyuki, Obara Wataru
Department of Urology, Iwate Medical University, Morioka-city, Japan.
Department of Urology, Iwate Medical University, Morioka-city, Japan.
Transl Oncol. 2021 Jan;14(1):100918. doi: 10.1016/j.tranon.2020.100918. Epub 2020 Oct 22.
This study aimed to identify novel prognostic biomarker for advanced renal cell carcinoma (RCC) patients treated with anti-PD-1 therapy, using quantitative multi-immunofluorescence (IF) analysis of tumor immunity. Twenty-five consecutive patients who had metastatic or unresectable RCC treated with anti-PD-1 therapy were studied. The patients were divided into a responder group (n = 12) and a non-responder group (n = 13). Quantitative multi-IF staining was performed on biopsy or surgical kidney samples using a panel of antibodies. Sections were scanned using a Mantra microscope, and the images were analyzed with inForm™ software. Responders had significantly higher rate of TIM3-positive tumor (100% versus 53.9%, p < 0.01) than non-responders. Multi-IF analysis showed that TIM3 expression on tumor cells was most strongly related to response to anti-PD-1 therapy, while some of the known immune-related prognostic factors in RCC (CD45RO, FOXP3, VEGF, PD-L1, PD-L2, CD163) had no significant association. Patients with TIM3-positive tumor showed significantly longer overall survival (not reached median time versus 6.0 months, p < 0.01) and progression-free survival (18.9 versus 1.1 months, p < 0.01) than those with TIM3-negative tumor. Immunohistochemistry study using samples obtained after anti-PD-1 therapy showed infiltration of CD163 macrophages and release of HMGB1, a ligand of TIM3, in necrotic tumor area. In conclusion, our study found clinical correlation between TIM3 expression on tumor cells and response to anti-PD-1 therapy. Further studies are warranted to verify whether TIM3 expression on tumor cells before systemic therapy predicts the efficacy of anti-PD-1 therapy for RCC in the clinical setting.
本研究旨在通过对肿瘤免疫进行定量多重免疫荧光（IF）分析，为接受抗PD-1治疗的晚期肾细胞癌（RCC）患者确定新的预后生物标志物。对连续25例接受抗PD-1治疗的转移性或不可切除RCC患者进行了研究。患者被分为应答组（n = 12）和无应答组（n = 13）。使用一组抗体对活检或手术切除的肾脏样本进行定量多重IF染色。切片用Mantra显微镜扫描，图像用inForm™软件分析。应答者的TIM3阳性肿瘤率（100%对53.9%，p < 0.01）显著高于无应答者。多重IF分析表明，肿瘤细胞上的TIM3表达与抗PD-1治疗反应最密切相关，而RCC中一些已知的免疫相关预后因素（CD45RO、FOXP3、VEGF、PD-L1、PD-L2、CD163）无显著关联。TIM3阳性肿瘤患者的总生存期（未达到中位时间对6.0个月，p < 0.01）和无进展生存期（18.9对1.1个月，p < 0.01）显著长于TIM3阴性肿瘤患者。使用抗PD-1治疗后获得的样本进行的免疫组织化学研究显示，坏死肿瘤区域有CD163巨噬细胞浸润和TIM3配体HMGB1释放。总之，我们的研究发现肿瘤细胞上的TIM3表达与抗PD-1治疗反应之间存在临床相关性。有必要进一步研究以验证全身治疗前肿瘤细胞上的TIM3表达是否能在临床环境中预测抗PD-1治疗对RCC的疗效。
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