Objective

Upper urinary tract urothelial carcinoma (UTUC) is a relatively uncommon disease with few reported molecular markers. This study evaluated Tim-3 and PD-1 expression in primary UTUC and its impact on patients' clinical outcomes.

Methods

Tim-3 and PD-1 protein expression was detected by immunohistochemistry in paraffin-embedded sections from 101 UTUC patients. The H-score was correlated with clinicopathologic outcomes and the long-term recurrence and survival rates.

Results

T cell immunoglobulin mucin-3 (Tim-3) protein was overexpressed in UTUC cells, especially tumour-infiltrating lymphocytes (TILs) and endothelial cells. We found that 95% (95/101) of UTUC tissues had dysregulated Tim-3 expression, of which 44% (44/101) showed high expression. High Tim-3 expression (H-score≥100) was significantly correlated with advanced pathological grade, advanced T stage and tumour recurrence (P=0.016, 0.001 and < 0.001, respectively) and with poor intravesical recurrence-free survival (IRFS) and overall survival (OS) (P< 0.001 and 0.003). Moreover, another immune checkpoint molecule, programmed death receptor-1 (PD-1), was also assessed in our study. Among patients in the low Tim-3 expression subgroup, those with high PD-1 expression experienced intravesical recurrence (IVR) more often than those with low PD-1 expression (P< 0.001). However, the PD-1 expression level had no effect on prognosis in the high Tim-3 expression subgroup.

Conclusion

We confirmed that high Tim-3 protein expression can be used as an indicator of earlier IVR and shorter OS in patients with UTUC, while high expression of PD-1 is only related to earlier IVR. We showed that Tim-3 plays a more important role in tumour recurrence and progression than PD-1. Collectively, our findings support the use of Tim-3 and PD-1 as clinical prognostic factors indicating poor patient survival. Tim-3, alone or in combination with PD-1, could become a target for future UTUC therapies, but further prospective studies are needed.

中文翻译：

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Tim-3和PD-1表达在上尿路尿路上皮癌预后中的预后及临床病理学意义

客观的

上尿路尿路上皮癌（UTUC）是一种相对少见的疾病，几乎没有报道的分子标志物。本研究评估了原发性 UTUC 中 Tim-3 和 PD-1 的表达及其对患者临床结果的影响。

方法

通过免疫组织化学在来自 101 名 UTUC 患者的石蜡包埋切片中检测到 Tim-3 和 PD-1 蛋白表达。H 评分与临床病理结果以及长期复发率和生存率相关。

结果

T 细胞免疫球蛋白粘蛋白 3 (Tim-3) 蛋白在 UTUC 细胞中过度表达，尤其是肿瘤浸润淋巴细胞 (TIL) 和内皮细胞。我们发现 95% (95/101) 的 UTUC 组织的 Tim-3 表达失调，其中 44% (44/101) 表现出高表达。Tim-3 高表达（H-score≥100）与晚期病理分级、晚期 T 分期和肿瘤复发显着相关（分别为P = 0.016、0.001 和 < 0.001），并且与较差的膀胱内无复发生存期（IRFS）和总生存期 (OS) ( P< 0.001 和 0.003)。此外，我们的研究还评估了另一种免疫检查点分子程序性死亡受体 1 (PD-1)。在 Tim-3 低表达亚组患者中，PD-1 高表达者比 PD-1 低表达者更易发生膀胱内复发（IVR）（P < 0.001）。然而，PD-1 表达水平对 Tim-3 高表达亚组的预后没有影响。

结论

我们证实，Tim-3 蛋白的高表达可作为 UTUC 患者早期 IVR 和较短 OS 的指标，而 PD-1 的高表达仅与早期 IVR 相关。我们发现 Tim-3 在肿瘤复发和进展中的作用比 PD-1 更重要。总的来说，我们的研究结果支持使用 Tim-3 和 PD-1 作为临床预后因素，表明患者存活率低。Tim-3，单独或与 PD-1 联合使用，可能成为未来 UTUC 治疗的靶点，但需要进一步的前瞻性研究。