一个 CTL/M2 巨噬细胞相关的四基因签名，用于预测接受辅助放疗的三阴性乳腺癌的无转移生存。

A CTL/M2 macrophage-related four-gene signature predicting metastasis-free survival in triple-negative breast cancer treated with adjuvant radiotherapy.

机构信息

Department of Cancer Center, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University), No. 10 Changjiang Zhilu, Yuzhong District, Chongqing, 400042, China.

出版信息

Breast Cancer Res Treat. 2021 Nov;190(2):329-341. doi: 10.1007/s10549-021-06379-1. Epub 2021 Sep 5.

DOI:10.1007/s10549-021-06379-1

PMID:34482483

Abstract

PURPOSE

This study aimed to develop and validate a prognostic model for metastasis-free survival (MFS) based on genes that may functionally interact with cytotoxic T lymphocytes (CTLs) and M2 macrophages in patients with triple-negative breast cancer (TNBC) who underwent adjuvant radiotherapy.

METHODS

The transcriptional and phenotypic profiles of TNBC and other breast cancer subtypes were downloaded from gene expression omnibus (GEO). The abundance of infiltrated immune cells was evaluated through CIBERSORTx or MCP-counter. A weighted linear model, the score for MFS (SMFS), was developed using the least absolute shrinkage and selection operator (LASSO) in GSE58812 and validated in GSE2034 and GSE12276. The biological implication of the SMFS was explored by evaluating its associations with TNBC molecular subtypes and other radiosensitivity- or immune-related signatures.

RESULTS

A model consisting of the PCDH12/ELP3, PCDH12/MSRA, and FAM160B2/MSRA gene expression ratios with non-zero coefficients finally selected by LASSO was developed using GSE58812. In GSE2034 (treatment with adjuvant radiotherapy), the SMFS was significantly associated with MFS in TNBC patients (hazard ratio (HR) = 8.767, 95% confidence interval (CI) 1.856-41.408, P = 0.006) and, to a lesser extent, in non-TNBC patients (HR = 2.888, 95% CI 1.076-7.750, P = 0.035). However, the interaction of subtype (TNBC vs non-TNBC) and the SMFS tended to be significant (P = 0.081). In contrast, the SMFS was not significantly associated with MFS in either TNBC patients (P = 0.499) or non-TNBC patients (P = 0.536) in GSE12276 (treatment without radiotherapy). Among the four TNBC molecular subtypes, the c1 and c4 subtypes exhibited higher CTL infiltration and lower SMFS values than the c2 and c3 subtypes. In addition, the SMFS was positively correlated with the abundance of endothelial cells (r = 0.413, P < 0.001).

CONCLUSION

The proposed model has the potential to predict MFS in TNBC patients after adjuvant radiotherapy, and the SMFS may represent a measurement of tumor immune suppression.

摘要

目的

本研究旨在开发和验证一种基于可能与接受辅助放疗的三阴性乳腺癌（TNBC）患者的细胞毒性 T 淋巴细胞（CTL）和 M2 巨噬细胞功能相互作用的基因的无转移生存（MFS）预后模型。

方法

从基因表达综合数据库（GEO）下载 TNBC 和其他乳腺癌亚型的转录组和表型谱。通过 CIBERSORTx 或 MCP-counter 评估浸润免疫细胞的丰度。使用最小绝对值收缩和选择算子（LASSO）在 GSE58812 中开发加权线性模型，即 MFS 评分（SMFS），并在 GSE2034 和 GSE12276 中进行验证。通过评估 SMFS 与 TNBC 分子亚型和其他放射敏感性或免疫相关特征的关联，探讨 SMFS 的生物学意义。

结果

使用 GSE58812 通过 LASSO 最终选择具有非零系数的 PCDH12/ELP3、PCDH12/MSRA 和 FAM160B2/MSRA 基因表达比组成的模型。在 GSE2034（接受辅助放疗治疗）中，SMFS 与 TNBC 患者的 MFS 显著相关（危险比（HR）=8.767，95%置信区间（CI）1.856-41.408，P=0.006），在非 TNBC 患者中也有一定程度的相关（HR=2.888，95%CI 1.076-7.750，P=0.035）。然而，亚型（TNBC 与非 TNBC）和 SMFS 的相互作用倾向于具有统计学意义（P=0.081）。相反，在 GSE12276（未接受放疗治疗）中，SMFS 与 TNBC 患者（P=0.499）或非 TNBC 患者（P=0.536）的 MFS 均无显著相关性。在四个 TNBC 分子亚型中，c1 和 c4 亚型比 c2 和 c3 亚型具有更高的 CTL 浸润和更低的 SMFS 值。此外，SMFS 与内皮细胞丰度呈正相关（r=0.413，P<0.001）。