Sun Xiangjie, Zhai Jie, Sun Baohua, Parra Edwin Roger, Jiang Mei, Ma Wencai, Wang Jing, Kang Anthony M, Kannan Kasthuri, Pandurengan Renganayaki, Zhang Shanyu, Solis Luisa Maren, Haymaker Cara L, Raso Maria Gabriela, Mendoza Perez Julia, Sahin Aysegul A, Wistuba Ignacio I, Yam Clinton, Litton Jennifer K, Yang Fei
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mod Pathol. 2022 May;35(5):601-608. doi: 10.1038/s41379-021-00973-w. Epub 2021 Nov 27.
Triple-negative breast cancer (TNBC) with high tumour-infiltrating lymphocytes (TILs) has been associated with a promising prognosis. To better understand the prognostic value of immune cell subtypes in TNBC, we characterised TILs and the interaction between tumour cells and immune cell subtypes. A total of 145 breast cancer tissues were stained by multiplex immunofluorescence (mIF), including panel 1 (PD-L1, PD-1, CD3, CD8, CD68 and CK) and panel 2 (Foxp3, Granzyme B, CD45RO, CD3, CD8 and CK). Phenotypes were analysed and quantified by pathologists using InForm software. We found that in the ER-negative (ER <1% and HER2-negative) group and the ER/PR-low positive (ER 1-9% and HER2-negative) group, 11.2% and 7.1% of patients were PD-L1 by the tumour cell score, 29.0% and 28.6% were PD-L1 by the modified immune cell score and 30.8% and 32.1% were PD-L1 by the combined positive score. We combined ER-negative and ER/PR-low positive cases for the survival analysis since a 10% cut-off is often used in clinical practice for therapeutic purposes. The densities of PD-L1 tumour cells (HR: 0.366, 95% CI: 0.138-0.970; p = 0.043) within the tumour compartment and CD3 immune cells in the total area (tumour and stromal compartments combined) (HR: 0.213, 95% CI: 0.070-0.642; p = 0.006) were favourable prognostic biomarkers for overall survival (OS) in TNBC. The density of effector/memory cytotoxic T cells (CD3CD8CD45RO) in the tumour compartment was an independent prognostic biomarker for OS (HR: 0.232, 95% CI: 0.086-0.628; p = 0.004) and DFS (HR: 0.183, 95% CI: 0.1301-0.744; p = 0.009) in TNBC. Interestingly, spatial data suggested that patients with a higher density of PD-L1 tumour cells had shorter cell-cell distances from tumour cells to cytotoxic T cells (p < 0.01). In conclusion, we found that phenotyping tumour immune cells by mIF is highly informative in understanding the immune microenvironment in TNBC. PD-L1 tumour cells, total T cells and effector/memory cytotoxic T cells are promising prognostic biomarkers in TNBC.
具有高肿瘤浸润淋巴细胞（TILs）的三阴性乳腺癌（TNBC）预后良好。为了更好地了解TNBC中免疫细胞亚型的预后价值，我们对TILs以及肿瘤细胞与免疫细胞亚型之间的相互作用进行了特征分析。总共145个乳腺癌组织通过多重免疫荧光（mIF）染色，包括面板1（PD-L1、PD-1、CD3、CD8、CD68和CK）和面板2（Foxp3、颗粒酶B、CD45RO、CD3、CD8和CK）。病理学家使用InForm软件对表型进行分析和定量。我们发现，在雌激素受体阴性（ER<1%且人表皮生长因子受体2阴性）组和ER/PR低阳性（ER 1-9%且人表皮生长因子受体2阴性）组中，分别有11.2%和7.1%的患者肿瘤细胞评分显示为PD-L1阳性，29.0%和28.6%的患者改良免疫细胞评分显示为PD-L1阳性，30.8%和32.1%的患者联合阳性评分显示为PD-L1阳性。由于临床实践中通常采用10%的临界值用于治疗目的，我们将ER阴性和ER/PR低阳性病例合并进行生存分析。肿瘤区域内PD-L1肿瘤细胞的密度（HR：0.366，95%CI：0.138-0.970；p = 0.043）以及肿瘤和基质区域总和中CD3免疫细胞的密度（HR：0.213，95%CI：0.070-0.642；p = 0.006）是TNBC总生存期（OS）的良好预后生物标志物。肿瘤区域内效应/记忆细胞毒性T细胞（CD3CD8CD45RO）的密度是TNBC总生存期（HR：0.232，95%CI：0.086-0.628；p = 0.004）和无病生存期（HR：0.183，95%CI：0.1301-0.744；p = 0.009）的独立预后生物标志物。有趣的是，空间数据表明，PD-L1肿瘤细胞密度较高的患者，肿瘤细胞与细胞毒性T细胞之间的细胞间距离较短（p<0.01）。总之，我们发现通过mIF对肿瘤免疫细胞进行表型分析对于了解TNBC的免疫微环境具有很高的信息量。PD-L1肿瘤细胞、总T细胞和效应/记忆细胞毒性T细胞是TNBC中有前景的预后生物标志物。
