State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Front Immunol. 2023 Jan 24;14:959868. doi: 10.3389/fimmu.2023.959868. eCollection 2023.
The leucine rich repeat containing 3B (LRRC3B) gene is a tumor suppressor gene involved in the anti-tumor immune microenvironment. Expression of LRRC3B and DNA methylation at the LRRC3B promoter region may serve as a useful marker to predict response to anti-PD-1 therapy. However, no studies have yet systematically explored the protective role of LRRC3B methylation in tumor progression and immunity.
Expression of LRRC3B of 33 cancer types in The Cancer Genome Atlas (TCGA) was downloaded from UCSC Xena (http://xena.ucsc.edu/). And, we evaluated the differential expression of LRRC3B according to tumor stage, overall survival, and characteristics of the tumor microenvironment. The immunotherapeutic cohorts included IMvigor21, GSE119144, and GSE72308 which were obtained from the Gene Expression Omnibus database. We conducted pearson correlation analysis of LRRC3B and tumor microenvironment (TME) in pan-cancer. Also, six immune cell types (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and tumor purity were analyzed using the Tumor IMmune Estimation Resource (TIMER1.0) (Tumor IMmune Estimation Resource (TIMER2.0). And, a "silencing score" model base on LRRC3B promoter methylation to predict overall survival (OS) by multivariate Cox regression analysis was constructed. Finally, the model was applied to predict anti-PD-1 therapy in non-small cell lung cancer (NSCLC) and breast cancer (BRCA).
LRRC3B expression associated with less tumor invasion, less severe tumor stage, and decreased metastasis. The inactivation of LRRC3B promoted the enrichment of immuneosuppressive cells, including myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), M2 subtype of tumor-associated macrophages (M2-TAMs), M1 subtype of tumor-associated macrophages (M1-TAMs), and regulatory T (Treg) cells. A high silencing score was significantly associated with immune inhibition, low expression of LRRC3B, poor patient survival, and activation of cancer-related pathways.
Our comprehensive analysis demonstrated the potential role of LRRC3B in the anti-tumor microenvironment, clinicopathological features of cancer, and disease prognosis. It suggested that LRRC3B methylation could be used as a powerful biomarker to predict immunotherapy responses in NSCLC and BRCA.
富含亮氨酸重复序列 3B（LRRC3B）基因是一种参与抗肿瘤免疫微环境的肿瘤抑制基因。LRRC3B 的表达和 LRRC3B 启动子区域的 DNA 甲基化可能是预测抗 PD-1 治疗反应的有用标志物。然而，目前尚无研究系统地探讨 LRRC3B 甲基化在肿瘤进展和免疫中的保护作用。
从 UCSC Xena（http://xena.ucsc.edu/）下载了 33 种癌症类型的 TCGA 中 LRRC3B 的表达。并根据肿瘤分期、总生存期和肿瘤微环境特征评估 LRRC3B 的差异表达。免疫治疗队列包括从基因表达综合数据库获得的 IMvigor21、GSE119144 和 GSE72308。我们在泛癌中进行了 LRRC3B 与肿瘤微环境（TME）的皮尔逊相关性分析。此外，使用肿瘤免疫估计资源（TIMER1.0）（肿瘤免疫估计资源（TIMER2.0））分析了六种免疫细胞类型（B 细胞、CD8+T 细胞、CD4+T 细胞、巨噬细胞、中性粒细胞和树突状细胞）和肿瘤纯度。通过多变量 Cox 回归分析构建了基于 LRRC3B 启动子甲基化的“沉默评分”模型，以预测总生存期（OS）。最后，该模型应用于预测非小细胞肺癌（NSCLC）和乳腺癌（BRCA）的抗 PD-1 治疗。
LRRC3B 表达与肿瘤侵袭性降低、肿瘤分期减轻和转移减少相关。LRRC3B 的失活促进了免疫抑制细胞的富集，包括髓系来源的抑制细胞（MDSCs）、癌症相关成纤维细胞（CAFs）、M2 型肿瘤相关巨噬细胞（M2-TAMs）、M1 型肿瘤相关巨噬细胞（M1-TAMs）和调节性 T（Treg）细胞。高沉默评分与免疫抑制、LRRC3B 低表达、患者生存不良和癌症相关途径激活显著相关。
我们的综合分析表明，LRRC3B 在抗肿瘤微环境、癌症临床病理特征和疾病预后中具有潜在作用。它表明 LRRC3B 甲基化可用作预测 NSCLC 和 BRCA 免疫治疗反应的强大生物标志物。
