Studies on immune checkpoint inhibitors targeting B7-CD28 family pathways in esophageal squamous cell carcinoma (ESCC) have shown promising results. However, a comprehensive understanding of B7-CD28 family members in ESCC is still limited. This study aimed to construct a novel B7-CD28 family-based prognosis system to predict survival in patients with ESCC. We collected 179 cases from our previously published microarray data and 86 cases with qPCR data. Specifically, 119 microarray data (GSE53624) were used as a training set, whereas the remaining 60 microarray data (GSE53622), all 179 microarray data (GSE53625) and an independent cohort with 86 qPCR data were used for validation. The underlying mechanism and immune landscape of the system were also explored using bioinformatics and immunofluorescence. We examined 13 well-defined B7-CD28 family members and identified 2 genes (ICSOLG and HHLA2) with the greatest prognostic value. A system based on the combination HHLA2 and ICOSLG (B7-CD28 signature) was constructed to distinguish patients as high- or low-risk of an unfavorable outcome, which was further confirmed as an independent prognostic factor. As expected, the signature was well validated in the entire cohort and in the independent cohort, as well as in different clinical subgroups. The signature was found to be closely related to immune-specific biological processes and pathways. Additionally, high-risk group samples demonstrated high infiltration of Tregs and fibroblasts and distinctive immune checkpoint panels. Collectively, we built the first, practical B7-CD28 signature for ESCC that could independently identify high-risk patients. Such information may help inform immunotherapy-based treatment decisions for patients with ESCC.

针对食管鳞状细胞癌 (ESCC) 中 B7-CD28 家族通路的免疫检查点抑制剂的研究已显示出可喜的结果。然而，对ESCC中B7-CD28家族成员的全面了解仍然有限。本研究旨在构建一种新的基于 B7-CD28 家族的预后系统来预测 ESCC 患者的生存率。我们从之前发布的微阵列数据中收集了 179 个病例，并从 qPCR 数据中收集了 86 个病例。具体来说，119 个微阵列数据 (GSE53624) 用作训练集，而其余 60 个微阵列数据 (GSE53622)、所有 179 个微阵列数据 (GSE53625) 和一个具有 86 个 qPCR 数据的独立队列用于验证。还使用生物信息学和免疫荧光探索了该系统的潜在机制和免疫景观。我们检查了 13 个定义明确的 B7-CD28 家族成员，并确定了 2 个具有最大预后价值的基因（ICSOLG 和 HHLA2）。构建了一个基于 HHLA2 和 ICOSLG（B7-CD28 特征）组合的系统，以区分患者不良结果的高风险或低风险，这进一步被证实为独立的预后因素。正如预期的那样，该特征在整个队列和独立队列以及不同的临床亚组中得到了很好的验证。发现该特征与免疫特异性生物过程和途径密切相关。此外，高风险组样本显示 Treg 和成纤维细胞的高度浸润以及独特的免疫检查点组。总的来说，我们为 ESCC 构建了第一个实用的 B7-CD28 签名，可以独立识别高危患者。