Department of Urology, Xiangya Hospital, Central South University, Changsha, China.
Immunobiology & Transplant Science Center, Houston Methodist Research Institute, Texas Medical Center, Houston, TX 77030, USA.
Theranostics. 2021 Jan 1;11(7):3089-3108. doi: 10.7150/thno.53649. eCollection 2021.
Siglec15 is an emerging target for normalization cancer immunotherapy. However, pan-cancer anti-Siglec15 treatment is not yet validated and the potential role of Siglec15 in bladder cancer (BLCA) remains elusive. We comprehensively evaluated the expression pattern and immunological role of Siglec15 using pan-cancer analysis based on RNA sequencing data obtained from The Cancer Genome Atlas. We then systematically correlated Siglec15 with immunological characteristics in the BLCA tumor microenvironment (TME), including immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), immune checkpoints, and T cell inflamed score. We also analyzed the role of Siglec15 in predicting the molecular subtype and the response to several treatment options in BLCA. Our results were validated in several public cohorts as well as our BLCA tumor microarray cohort, the Xiangya cohort. We developed an immune risk score (IRS), validated it, and tested its ability to predict the prognosis and response to cancer immunotherapy. We found that Siglec15 was specifically overexpressed in the TME of various cancers. We hypothesize that Siglec15 designs a non-inflamed TME in BLCA based on the evidence that Siglec15 negatively correlated with immunomodulators, TIICs, cancer immunity cycles, immune checkpoints, and T cell inflamed score. Bladder cancer with high Siglec15 expression was not sensitive to cancer immunotherapy, but exhibited a higher incidence of hyperprogression. High Siglec15 levels indicated a luminal subtype of BLCA characterized by lower immune infiltration, lower response to cancer immunotherapy and neoadjuvant chemotherapy, but higher response to anti-angiogenic therapy and targeted therapies such as blocking Siglec15, β-catenin, PPAR-γ, and FGFR3 pathways. Notably, a combination of anti-Siglec15 and cancer immunotherapy may be a more effective strategy than monotherapy. IRS can accurately predict the prognosis and response to cancer immunotherapy. Anti-Siglec15 immunotherapy might be suitable for BLCA treatment as Siglec15 correlates with a non-inflamed TME in BLCA. Siglec15 could also predict the molecular subtype and the response to several treatment options.
Siglec15 是一种新兴的癌症免疫治疗正常化靶点。然而，泛癌种抗 Siglec15 治疗尚未得到验证，Siglec15 在膀胱癌（BLCA）中的潜在作用仍不清楚。我们使用基于癌症基因组图谱（TCGA）获得的 RNA 测序数据进行泛癌分析，全面评估了 Siglec15 的表达模式和免疫作用。然后，我们系统地将 Siglec15 与 BLCA 肿瘤微环境（TME）中的免疫特征相关联，包括免疫调节剂、癌症免疫周期、肿瘤浸润免疫细胞（TIIC）、免疫检查点和 T 细胞炎症评分。我们还分析了 Siglec15 在预测 BLCA 分子亚型和对几种治疗选择反应中的作用。我们的结果在几个公共队列以及我们的 BLCA 肿瘤微阵列队列（湘雅队列）中得到了验证。我们开发了一种免疫风险评分（IRS），对其进行了验证，并测试了其预测预后和对癌症免疫治疗反应的能力。我们发现 Siglec15 在各种癌症的 TME 中特异性过表达。我们假设 Siglec15 根据 Siglec15 与免疫调节剂、TIIC、癌症免疫周期、免疫检查点和 T 细胞炎症评分呈负相关的证据，在 BLCA 中设计了一个非炎症性的 TME。高 Siglec15 表达的膀胱癌对癌症免疫治疗不敏感，但表现出更高的超进展发生率。高 Siglec15 水平表明 BLCA 为 luminal 亚型，其特征为免疫浸润较低、对癌症免疫治疗和新辅助化疗的反应较低，但对抗血管生成治疗和靶向治疗（如阻断 Siglec15、β-catenin、PPAR-γ 和 FGFR3 途径）的反应较高。值得注意的是，抗 Siglec15 免疫治疗与癌症免疫治疗联合可能比单药治疗更有效。IRS 可以准确预测癌症免疫治疗的预后和反应。抗 Siglec15 免疫治疗可能适合 BLCA 治疗，因为 Siglec15 与 BLCA 中的非炎症性 TME 相关。Siglec15 还可以预测分子亚型和对几种治疗选择的反应。
