Riaz Nazia, Burugu Samantha, Cheng Angela S, Leung Samuel C Y, Gao Dongxia, Nielsen Torsten O
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada.
Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi 74800, Pakistan.
Cancers (Basel). 2021 Nov 18;13(22):5769. doi: 10.3390/cancers13225769.
Colony-stimulating factor-1 receptor (CSF-1R) signaling promotes an immune suppressive microenvironment enriched in M2 macrophages. Given that CSF-1R inhibitors are under investigation in clinical trials, including in breast cancer, CSF-1R expression and association with immune biomarkers could identify patients who derive greater benefit from combination with immunotherapies. TIMER2.0 and bc-GenExMiner v4.7 were used to assess the correlation of mRNA with immune infiltrates and prognosis. Following a prespecified training-validation approach, an optimized immunohistochemistry assay was applied to assess CSF-1R on carcinoma cells and macrophages on breast cancer tissue microarray series representing 2384 patients, coupled to comprehensive clinicopathological, biomarker, and outcome data. Significant positive correlations were observed between mRNA and immune infiltrates. High carcinoma CSF-1R correlated with grade 3 tumors >2 cm, hormone receptor negativity, high Ki67, immune checkpoint biomarkers, and macrophages expressing CSF-1R and CD163. High carcinoma CSF-1R was significantly associated with poor survival in univariate and multivariate analyses. Adverse prognostic associations were retained in ER+ cases regardless of the presence of CD8+ T cells. CSF-1R+ macrophages were not prognostic. High carcinoma CSF-1R is associated with aggressive breast cancer biology and poor prognosis, particularly in ER+ cases, and identifies patients in whom biomarker-directed CSF-1R therapies may yield superior therapeutic responses.
集落刺激因子-1受体（CSF-1R）信号传导促进富含M2巨噬细胞的免疫抑制微环境。鉴于CSF-1R抑制剂正在包括乳腺癌在内的临床试验中进行研究，CSF-1R表达及其与免疫生物标志物的关联可以识别出从与免疫疗法联合中获益更大的患者。使用TIMER2.0和bc-GenExMiner v4.7评估mRNA与免疫浸润及预后的相关性。按照预先指定的训练-验证方法，应用优化的免疫组织化学检测法评估代表2384例患者的乳腺癌组织微阵列系列中癌细胞和巨噬细胞上的CSF-1R，并结合全面的临床病理、生物标志物和结局数据。观察到mRNA与免疫浸润之间存在显著正相关。癌细胞高表达CSF-1R与肿瘤分级为3级且肿瘤大小>2 cm、激素受体阴性、Ki67高表达、免疫检查点生物标志物以及表达CSF-1R和CD163的巨噬细胞相关。在单因素和多因素分析中，癌细胞高表达CSF-1R与较差的生存率显著相关。无论是否存在CD8+ T细胞，ER+病例中均保留不良预后关联。CSF-1R+巨噬细胞无预后意义上的关联。癌细胞高表达CSF-1R与侵袭性乳腺癌生物学行为及不良预后相关，尤其是在ER+病例当中，并且可以识别出生化标志物导向的CSF - 1R疗法可能产生更好治疗反应的患者群体。
