肿瘤细胞治疗研究
英文原题：CD93 orchestrates the tumor microenvironment and predicts the molecular subtype and therapy response of bladder cancer.
CD93在肿瘤免疫调节中发挥关键作用。CD93表达提示BLCA更具侵袭性的临床病理状态和分子亚型，以及更差的治疗反应，这意味着在临床实践中将抗CD93治疗与免疫治疗（或化疗）联合可能对BLCA具有潜在益处。
CD93 新近被报道可使血管正常化并减弱胰腺癌治疗反应，但其在膀胱癌（BLCA）中的作用尚不清楚。
分析CD93在TCGA泛癌中的免疫学作用。在TCGA-BLCA和其他两个BLCA队列中评估CD93与BLCA临床及肿瘤微环境特征、预测的免疫治疗通路、分子亚型、治疗特征和突变状态之间的相关性。通过五个真实世界队列验证CD93对免疫治疗反应的影响，并用IC50评估化疗反应。基于CD93的风险模型通过LASSO回归构建，并由七个独立队列验证。
CD93 在泛癌中与免疫调节因子、TIL（肿瘤浸润淋巴细胞）（TILs）和免疫检查点呈正相关。在 BLCA 中，CD93 导致更高的 T 细胞炎症评分和免疫检查点表达。然而，CD93 提示更具侵袭性的临床特征、更差的生存、更多肿瘤相关巨噬细胞和调节性 T 细胞募集、T 细胞对癌细胞的识别和杀伤减少、预测的化疗和免疫治疗反应更低，这进一步被免疫治疗队列验证（IMvigor210：16.11% vs 29.53%；GSE176307：15.56% vs 20.93%）。值得注意的是，CD93 与富集的神经内分泌亚型和上皮-间充质转化分化相关，而 CD93 低表达组则富集 luminal 亚型。缺氧和 Wnt-β-catenin 等通路随 CD93 表达而富集，同时观察到更频繁的 FGFR3 突变。最后，基于 CD93 的风险模型经七个独立队列验证，在区分 BLCA 生存概率方面具有很强的能力（3 年 AUC 0.808）。
BACKGROUND: CD93 is newly reported to normalize vasculature and attenuate pancreatic cancer therapy response, but its role in bladder cancer (BLCA) is unknown. METHOD: The immunologic role of CD93 is analyzed across TCGA pan-cancers. The correlation between CD93 and BLCA clinical and tumor microenvironment features, predicted immunotherapy pathways, molecular subtypes, therapeutic signatures and mutation status was evaluated in TCGA-BLCA and other two BLCA cohorts. The impact of CD93 on immunotherapy response was validated by five real-world cohorts, and chemotherapy response was assessed with IC50. CD93-based risk model was constructed with LASSO regression and validated by seven independent cohorts. RESULT: CD93 is positively correlated with immunomodulators, tumor-infiltrating lymphocytes (TILs) and immune checkpoints across pan-cancers. In BLCA, CD93 leads to higher T cell inflamed score and expression of immune checkpoints. However, CD93 is indicative of more aggressive clinical features, worse survival, more tumor-associated macrophages and regulatory T cells recruitment, less recognition and killing of cancer cells by T cells, lower predicted chemotherapy and immunotherapy response, which is further validated by immunotherapy cohorts (IMvigor210: 16.11% vs 29.53%; GSE176307: 15.56% vs 20.93%). Notably, CD93 correlates with enriched neuroendocrine subtype and epithelial-mesenchymal transition differentiation, while CD93-low group has enriched luminal subtype. Pathways including hypoxia and Wnt-β-catenin are enriched along with CD93 expression, and more frequent FGFR3 mutation is also observed. Lastly, the CD93-based risk model, validated by seven independent cohorts, is powerful in distinguishing the survival probability of BLCA (3-year AUC 0.808). CONCLUSION: CD93 plays a critical role in tumor immune regulation. CD93 expression indicates more aggressive clinicopathological status and molecular subtypes of BLCA and worse therapy response, which implies that combing anti-CD93 therapy with immunotherapy (or chemotherapy) may be potentially beneficial for BLCA in clinical practice.
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