Background

Multi-omics analyses of muscle-invasive bladder cancer (MIBC) demonstrated that specific patterns of tumor infiltrating lymphocytes (TILs) associates with improved outcomes in patients treated with radical cystectomy. However, methodologies for simple and robust quantification of TILs, especially for daily practice purposes, are lacking. Thus, we investigated the feasibility of stromal TIL scoring on hematoxylin/eosin stained (HE) slides in MIBC.

Materials and methods

sTILs were scored on HE whole slides of 241 MIBC patients treated with radical cystectomy and adjuvant chemotherapy. Median infiltration of 10% was used as objective cut-off. Additionally, immunohistochemistry was performed on spatially organized tissue microarrays to quantify key immune cell populations objectively for correlational analyses with sTIL scoring results (CD3⁺/Pan-T-cells, CD8⁺/cytotoxic T-Cells, CD56⁺/NK-cells, CD68⁺/macrophages). sTILs amounts were correlated with clinicopathological features, recurrence-free (RFS), disease-specific (DSS), and overall survival (OS).

Results

sTIL amounts correlated moderately to strongly with quantitatively estimated amounts of pan-T-cells (r = 0.73, P <0.0001), cytotoxic T-cells (r = 0.73, P <0.0001), NK-cells (r = 0.68, P <0.0001), macrophages (r = 0.55, P <0.0001) and with pan-cytotoxic immune infiltration (r = 0.78, P <0.0001), thus reflecting overall infiltration with key immune cell populations. sTIL infiltration ≥10% was associated with significantly higher 5-year OS (45.5% vs. 19.8%), DSS (56.6% vs. 25.6%) and RFS (56.2% vs. 18.9%; P <0.0001 for all three comparisons) rates, and lower pT-stage (P = 0.015), lower pN-stage (P = 0.028), lower rates of lymphovascular invasion (P = 0.0003) and blood vessel invasion (P = 0.01) when compared to sTIL infiltration of <10%. Multivariable regressions models confirmed sTILs as strongest independent predictor for improved outcomes following radical cystectomy.

Conclusions

HE based sTIL scoring is a reliable tool to assess MIBC inflammation status and to stratify the survival of MIBC patients undergoing radical cystectomy. sTIL amount is an independent predictor for improved survival, and might be an useful, routinely applicable tool to identify patients benefiting from perioperative platinum-based chemotherapy and checkpoint inhibitor therapy. However, external validation of our data is required.

中文翻译：

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间质瘤浸润淋巴细胞评分 (sTILs) 在根治性膀胱切除术后肌肉浸润性膀胱尿路上皮癌患者风险分层中的效用

背景

对肌肉浸润性膀胱癌 (MIBC) 的多组学分析表明，肿瘤浸润淋巴细胞 (TIL) 的特定模式与接受根治性膀胱切除术的患者的预后改善相关。然而，缺乏对 TIL 进行简单和稳健量化的方法，特别是用于日常实践目的的方法。因此，我们研究了在 MIBC 中对苏木精/伊红染色 (HE) 载玻片进行基质 TIL 评分的可行性。

材料和方法

sTILs 在 241 名接受根治性膀胱切除术和辅助化疗的 MIBC 患者的 HE 全切片上进行评分。10% 的中值浸润被用作目标截止值。此外，免疫组织化学在空间组织的组织微阵列上进行，以客观地量化关键免疫细胞群，用于与 sTIL 评分结果（CD3 ⁺ /Pan-T 细胞、CD8 ⁺ /细胞毒性 T 细胞、CD56 ⁺ /NK 细胞、CD68 ⁺ /巨噬细胞）。sTILs 量与临床病理学特征、无复发 (RFS)、疾病特异性 (DSS) 和总生存期 (OS) 相关。

结果

sTIL 量与定量估计的泛 T 细胞（r = 0.73，P <0.0001）、细胞毒性 T 细胞（r = 0.73，P <0.0001）、NK 细胞（r = 0.68，P < 0.0001)、巨噬细胞 (r = 0.55, P <0.0001) 和泛细胞毒性免疫浸润 (r = 0.78, P <0.0001)，因此反映了关键免疫细胞群的整体浸润。sTIL 浸润≥10% 与显着更高的 5 年 OS（45.5% 对 19.8%）、DSS（56.6% 对 25.6%）和 RFS（56.2% 对 18.9%；所有三个比较的P <0.0001）相关率，较低的 pT 阶段 ( P  = 0.015)，较低的 pN 阶段 ( P = 0.028）， 与小于 10% 的 sTIL 浸润相比，淋巴血管浸润（ P  = 0.0003）和血管浸润（P = 0.01）的发生率较低。多变量回归模型证实 sTILs 是根治性膀胱切除术后改善结果的最强独立预测因子。

结论

基于 HE 的 sTIL 评分是评估 MIBC 炎症状态和对接受根治性膀胱切除术的 MIBC 患者的生存进行分层的可靠工具。sTIL 量是提高生存率的独立预测因子，可能是一种有用的、常规适用的工具，可用于确定受益于围手术期铂类化疗和检查点抑制剂治疗的患者。但是，需要对我们的数据进行外部验证。