鉴定胆管癌的肿瘤抗原和免疫亚型，用于 mRNA 疫苗的开发。

BACKGROUND: The mRNA-based cancer vaccine has been considered a promising strategy and the next hotspot in cancer immunotherapy. However, its application on cholangiocarcinoma remains largely uncharacterized. This study aimed to identify potential antigens of cholangiocarcinoma for development of anti-cholangiocarcinoma mRNA vaccine, and determine immune subtypes of cholangiocarcinoma for selection of suitable patients from an extremely heterogeneous population. METHODS: Gene expression profiles and corresponding clinical information were collected from GEO and TCGA, respectively. cBioPortal was used to visualize and compare genetic alterations. GEPIA2 was used to calculate the prognostic index of the selected antigens. TIMER was used to visualize the correlation between the infiltration of antigen-presenting cells and the expression of the identified antigens. Consensus clustering analysis was performed to identify the immune subtypes. Graph learning-based dimensionality reduction analysis was conducted to visualize the immune landscape of cholangiocarcinoma. RESULTS: Three tumor antigens, such as CD247, FCGR1A, and TRRAP, correlated with superior prognoses and infiltration of antigen-presenting cells were identified in cholangiocarcinoma. Cholangiocarcinoma patients were stratified into two immune subtypes characterized by differential molecular, cellular and clinical features. Patients with the IS1 tumor had immune "hot" and immunosuppressive phenotype, whereas those with the IS2 tumor had immune "cold" phenotype. Interestingly, patients with the IS2 tumor had a superior survival than those with the IS1 tumor. Furthermore, distinct expression of immune checkpoints and immunogenic cell death modulators was observed between different immune subtype tumors. Finally, the immune landscape of cholangiocarcinoma revealed immune cell components in individual patient. CONCLUSIONS: CD247, FCGR1A, and TRRAP are potential antigens for mRNA vaccine development against cholangiocarcinoma, specifically for patients with IS2 tumors. Therefore, this study provides a theoretical basis for the anti-cholangiocarcinoma mRNA vaccine and defines suitable patients for vaccination.

背景：基于 mRNA 的癌症疫苗被认为是一种有前途的策略，也是癌症免疫治疗的下一个热点。然而，其在胆管癌中的应用仍很大程度上尚未被描述。本研究旨在确定胆管癌的潜在抗原，用于开发抗胆管癌 mRNA 疫苗，并确定胆管癌的免疫亚型，以便从极度异质的人群中选择合适的患者。

方法：从 GEO 和 TCGA 分别收集基因表达谱和相应的临床信息。使用 cBioPortal 可视化和比较遗传改变。使用 GEPIA2 计算选定抗原的预后指数。使用 TIMER 可视化抗原呈递细胞浸润与鉴定抗原表达之间的相关性。进行共识聚类分析以确定免疫亚型。进行基于图学习的降维分析以可视化胆管癌的免疫景观。

结果：在胆管癌中鉴定出三个与较好预后相关且抗原呈递细胞浸润的肿瘤抗原，如 CD247、FCGR1A 和 TRRAP。将胆管癌患者分为两个免疫亚型，其特征在于不同的分子、细胞和临床特征。具有 IS1 肿瘤的患者具有免疫“热”和免疫抑制表型，而具有 IS2 肿瘤的患者具有免疫“冷”表型。有趣的是，具有 IS2 肿瘤的患者的生存优于具有 IS1 肿瘤的患者。此外，在不同免疫亚型的肿瘤之间观察到免疫检查点和免疫原性细胞死亡调节剂的不同表达。最后，胆管癌的免疫景观揭示了个体患者的免疫细胞成分。

结论：CD247、FCGR1A 和 TRRAP 是针对胆管癌的 mRNA 疫苗开发的潜在抗原，特别是针对 IS2 肿瘤的患者。因此，本研究为抗胆管癌 mRNA 疫苗提供了理论基础，并为疫苗接种定义了合适的患者。