Primary esophageal small cell carcinoma (PESCC) is a weakly prevalent but lethal malignancy with early metastasis and a poor prognosis. Currently, neither effective prognostic indicators nor curative therapies are available for PESCC. Immunotherapy has now evolved into one of the most promising therapies for cancer patients. Tumor-infiltrating immune cells which are integral to the tumor immune microenvironment (TIME) are recognized as highly important for prognosis prediction, while the responsiveness to immune checkpoint blockade may be subject to the features of TIME. In this study, we aim to identify the TIME and provide indication for the applicability of immune checkpoint therapy in PESCC. We found that PD-L1 expression was detected in 33.33% (27/81) of all the patients, mostly exhibiting a stroma-only pattern and that it was positively associated with tumor-infiltrating immune cells (CD4⁺, CD8⁺, and CD163⁺). In 74.07% of PD-L1-positive specimens, PD-L1⁺CD163⁺ cells were colocalized more with CD4⁺ than CD8⁺ T cells. 83.95% (68/81) of all the specimens were infiltrated with more CD4⁺ than CD8⁺ T cells. Further analysis showed FoxP3⁺ Tregs constituted 13-27% of the total CD4⁺ T cell population. The Kaplan-–Meier analysis indicated several factors that contribute to poor survival, including negative PD-L1 expression, rich CD4 expression, rich FoxP3 expression, a low CD8/CD4 ratio, and a high FoxP3/CD8 ratio. A nomogram model was constructed and showed good performance for survival prediction. These results highlight that a suppressive TIME contributes to poor survival of patients with PESCC. TIME analyses might be a promising approach to evaluate the possibility and effect of immune checkpoint-based immunotherapeutics in PESCC patients.

中文翻译：

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肿瘤浸润免疫细胞和 PD-L1 作为原发性食管小细胞癌的预后生物标志物

原发性食管小细胞癌 (PESCC) 是一种发病率较弱但致命的恶性肿瘤，具有早期转移和不良预后。目前，对于 PESCC 既没有有效的预后指标，也没有治愈性的治疗方法。免疫疗法现已发展成为癌症患者最有希望的疗法之一。肿瘤免疫微环境 (TIME) 不可或缺的肿瘤浸润免疫细胞被认为对预后预测非常重要，而对免疫检查点阻断的反应可能受 TIME 特征的影响。在本研究中，我们旨在确定 TIME 并为免疫检查点治疗在 PESCC 中的适用性提供指示。我们发现所有患者中有 33.33% (27/81) 检测到 PD-L1 表达，⁺、CD8 ⁺和 CD163 ⁺）。在 74.07% 的 PD-L1 阳性标本中，PD-L1 ⁺ CD163 ⁺细胞与 CD4 ^{+ 的}共定位比 CD8 ⁺ T 细胞更多。所有样品的83.95％（81分之68）与更浸润CD4 ⁺比CD8 ⁺ T细胞。进一步分析显示 FoxP3 ⁺ Tregs 占 CD4 ⁺总量的 13-27%T细胞群。Kaplan--Meier 分析表明导致生存率低的几个因素，包括阴性 PD-L1 表达、丰富的 CD4 表达、丰富的 FoxP3 表达、低 CD8/CD4 比率和高 FoxP3/CD8 比率。构建了列线图模型并显示出良好的生存预测性能。这些结果强调了抑制性 TIME 导致 PESCC 患者的生存率低。时间分析可能是评估基于免疫检查点的免疫疗法在 PESCC 患者中的可能性和效果的一种有前景的方法。