Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Front Immunol. 2022 Apr 4;13:855849. doi: 10.3389/fimmu.2022.855849. eCollection 2022.
This study aimed to establish a novel quantification system of ferroptosis patterns and comprehensively analyze the relationship between ferroptosis score (FS) and the immune cell infiltration (ICI) characterization, tumor mutation burden (TMB), prognosis, and therapeutic sensitivity in left-sided and right-sided colon cancers (LCCs and RCCs, respectively).
We comprehensively evaluated the ferroptosis patterns in 444 LCCs and RCCs based on 59 ferroptosis-related genes (FRGs). The FS was constructed to quantify ferroptosis patterns by using principal component analysis algorithms. Next, the prognostic value and therapeutic sensitivities were evaluated using multiple methods. Finally, we performed weighted gene co-expression network analysis (WGCNA) to identify the key FRGs. The IMvigor210 cohort, TCGA-COAD proteomics cohort, and Immunophenoscores were used to verify the predictive abilities of FS and the key FRGs.
Two ferroptosis clusters were determined. Ferroptosis cluster B demonstrated a high degree of congenital ICI and stromal-related signal enrichment with a poor prognosis. The prognosis, response of targeted inhibitors, and immunotherapy were significantly different between high and low FS groups (HSG and LSG, respectively). HSG was characterized by high TMB and microsatellite instability-high subtype with poor prognosis. Meanwhile, LSG was more likely to benefit from immunotherapy. ALOX5 was identified as a key FRG based on FS. Patients with high protein levels of ALOX5 had poorer prognoses.
This work revealed that the evaluation of ferroptosis subtypes will contribute to gaining insight into the heterogeneity in LCCs and RCCs. The quantification for ferroptosis patterns played a non-negligible role in predicting ICI characterization, prognosis, and individualized immunotherapy strategies.
本研究旨在建立一种新的铁死亡模式定量系统，并全面分析铁死亡评分（FS）与左、右侧结肠癌（LCC 和 RCC）中免疫细胞浸润（ICI）特征、肿瘤突变负担（TMB）、预后和治疗敏感性之间的关系。
我们基于 59 个铁死亡相关基因（FRGs），综合评估了 444 例 LCC 和 RCC 中的铁死亡模式。采用主成分分析算法构建 FS，以定量铁死亡模式。然后，采用多种方法评估预后价值和治疗敏感性。最后，我们进行加权基因共表达网络分析（WGCNA），以识别关键 FRGs。IMvigor210 队列、TCGA-COAD 蛋白质组学队列和 Immunophenoscores 用于验证 FS 和关键 FRGs 的预测能力。
确定了两个铁死亡簇。铁死亡簇 B 表现出高度先天性 ICI 和基质相关信号富集，预后不良。高低 FS 组（HSG 和 LSG）之间的预后、靶向抑制剂反应和免疫治疗的反应有显著差异。HSG 以高 TMB 和微卫星不稳定高亚型为特征，预后不良。同时，LSG 更有可能受益于免疫治疗。基于 FS，ALOX5 被鉴定为关键 FRG。ALOX5 蛋白水平高的患者预后较差。
本研究揭示了评估铁死亡亚型将有助于深入了解 LCC 和 RCC 的异质性。铁死亡模式的定量在预测 ICI 特征、预后和个体化免疫治疗策略方面发挥了不可忽视的作用。
