Laboratorio de Investigación en Cáncer, Fundación para el progreso de la Medicina, X5000EMS, Córdoba, Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Breast Cancer Res. 2021 Mar 25;23(1):40. doi: 10.1186/s13058-021-01418-7.
Characterization of breast cancer (BC) through the determination of conventional markers such as ER, PR, HER2, and Ki67 has been useful as a predictive and therapeutic tool. Also, assessment of tumor-infiltrating lymphocytes has been proposed as an important prognostic aspect to be considered in certain BC subtypes. However, there is still a need to identify additional biomarkers that could add precision in distinguishing therapeutic response of individual patients. To this end, we focused in the expression of interferon regulatory factor 8 (IRF8) in BC cells. IRF8 is a transcription factor which plays a well-determined role in myeloid cells and that seems to have multiple antitumoral roles: it has tumor suppressor functions; it acts downstream IFN/STAT1, required for the success of some therapeutic regimes, and its expression in neoplastic cells seems to depend on a cross talk between the immune contexture and the tumor cells. The goal of the present study was to examine the relationship between IRF8 with the therapeutic response and the immune contexture in BC, since its clinical significance in this type of cancer has not been thoroughly addressed.
We identified the relationship between IRF8 expression and the clinical outcome of BC patients and validated IRF8 as predictive biomarker by using public databases and then performed in silico analysis. To correlate the expression of IRF8 with the immune infiltrate in BC samples, we performed quantitative multiplex immunohistochemistry.
IRF8 expression can precisely predict the complete pathological response to monoclonal antibody therapy or to select combinations of chemotherapy such as FAC (fluorouracil, adriamycin, and cytoxan) in ER-negative BC subtypes. Analysis of immune cell infiltration indicates there is a strong correlation between activated and effector CD8 T cell infiltration and tumoral IRF8 expression.
We propose IRF8 expression as a potent biomarker not only for prognosis, but also for predicting therapy response in ER-negative BC phenotypes. Its expression in neoplastic cells also correlates with CD8 T cell activation and infiltration. Therefore, our results justify new efforts towards understanding mechanisms regulating IRF8 expression and how they can be therapeutically manipulated.
通过测定 ER、PR、HER2 和 Ki67 等常规标志物对乳腺癌 (BC) 进行特征描述，已被证明是一种具有预测和治疗价值的工具。此外，肿瘤浸润淋巴细胞的评估已被提议作为某些 BC 亚型的重要预后因素。然而，仍有必要确定其他生物标志物，以提高区分个体患者治疗反应的精确性。为此，我们专注于 BC 细胞中干扰素调节因子 8 (IRF8) 的表达。IRF8 是一种转录因子，在髓细胞中发挥着明确的作用，并且似乎具有多种抗肿瘤作用：它具有肿瘤抑制功能；它作为下游 IFN/STAT1 的作用，对于某些治疗方案的成功是必需的，并且其在肿瘤细胞中的表达似乎依赖于免疫结构与肿瘤细胞之间的串扰。本研究的目的是研究 IRF8 与 BC 治疗反应和免疫结构之间的关系，因为其在这种类型的癌症中的临床意义尚未得到充分解决。
我们确定了 IRF8 表达与 BC 患者临床结局之间的关系，并通过使用公共数据库验证了 IRF8 作为预测生物标志物，然后进行了计算机分析。为了将 IRF8 的表达与 BC 样本中的免疫浸润相关联，我们进行了定量多重免疫组化分析。
IRF8 表达可以精确预测单克隆抗体治疗或选择 FAC（氟尿嘧啶、阿霉素和环磷酰胺）等化疗组合对 ER 阴性 BC 亚型的完全病理反应。免疫细胞浸润分析表明，活化和效应 CD8 T 细胞浸润与肿瘤 IRF8 表达之间存在很强的相关性。
我们提出 IRF8 表达不仅是一种强有力的预后生物标志物，而且是预测 ER 阴性 BC 表型治疗反应的生物标志物。其在肿瘤细胞中的表达也与 CD8 T 细胞的激活和浸润相关。因此，我们的结果证明了为理解调节 IRF8 表达的机制以及如何对其进行治疗性操纵而进行新的努力是合理的。
