Clinical Pharmacology and Pharmacogenomics Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
Department of Surgery, Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt.
Int J Mol Sci. 2023 Sep 19;24(18):14254. doi: 10.3390/ijms241814254.
Breast cancer (BC) is not only a mass of malignant cells but also a systemic inflammatory disease. BC pro-tumorigenic inflammation has been shown to promote immune evasion and provoke BC progression. The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is activated when pattern recognition receptors (PRRs) sense danger signals such as calreticulin (CALR) from damaged/dying cells, leading to the secretion of interleukin-1β (IL-1β). CALR is a novel BC biological marker, and its high levels are associated with advanced tumors. NLRP3 expression is strongly correlated with an elevated proliferative index Ki67, BC progression, metastasis, and recurrence in patients with hormone receptor-positive (HR+) and triple-negative BC (TNBC). Tumor-associated macrophages (TAMs) secrete high levels of IL-1β promoting endocrine resistance in HR+ BC. Recently, an immunosuppressive soluble form of programmed death ligand 1 (sPD-L1) has been identified as a novel prognostic biomarker in triple-negative breast cancer (TNBC) patients. Interestingly, IL-1β induces sPD-L1 release. BC Patients with elevated IL-1β and sPD-L1 levels show significantly short progression-free survival. For the first time, this study aims to investigate the inhibitory impact of thymoquinone (TQ) on CALR, the NLRP3 pathway and sPD-L1 in HR+ and TNBC. Blood samples were collected from 45 patients with BC. The effect of differing TQ concentrations for different durations on the expression of CALR, NLRP3 complex components and IL-1β as well as the protein levels of sPD-L1 and IL-1β were investigated in the peripheral blood mononuclear cells (PBMCs) and TAMs of TNBC and HR+ BC patients, respectively. The findings showed that TQ significantly downregulated the expression of CALR, NLRP3 components and IL-1β together with the protein levels of secreted IL-1β and sPD-L1. The current findings demonstrated novel immunomodulatory effects of TQ, highlighting its potential role not only as an excellent adjuvant but also as a possible immunotherapeutic agent in HR+ and TNBC patients.
乳腺癌（BC）不仅是一团恶性细胞，还是一种系统性炎症性疾病。BC 致瘤性炎症已被证明可促进免疫逃逸并引发 BC 进展。当模式识别受体（PRRs）感知到来自受损/死亡细胞的钙网蛋白（CALR）等危险信号时，NOD 样受体（NLR）家族包含吡啶结构域蛋白 3（NLRP3）炎性小体被激活，导致白细胞介素-1β（IL-1β）的分泌。CALR 是一种新的 BC 生物标志物，其高水平与晚期肿瘤相关。NLRP3 表达与激素受体阳性（HR+）和三阴性乳腺癌（TNBC）患者的高增殖指数 Ki67、BC 进展、转移和复发强烈相关。肿瘤相关巨噬细胞（TAMs）分泌高水平的 IL-1β，促进 HR+BC 的内分泌抵抗。最近，一种免疫抑制性程序性死亡配体 1（sPD-L1）的可溶性形式已被确定为 TNBC 患者的一种新的预后生物标志物。有趣的是，IL-1β诱导 sPD-L1 的释放。BC 患者中升高的 IL-1β和 sPD-L1 水平显示出明显的无进展生存期缩短。本研究首次旨在研究胸腺醌（TQ）对 HR+和 TNBC 中 CALR、NLRP3 途径和 sPD-L1 的抑制作用。从 45 名 BC 患者中采集血样。分别研究了不同浓度 TQ 作用不同时间对 TNBC 和 HR+BC 患者外周血单个核细胞（PBMCs）和 TAMs 中 CALR、NLRP3 复合物成分和 IL-1β以及分泌的 IL-1β和 sPD-L1 蛋白水平的影响。结果表明，TQ 可显著下调 CALR、NLRP3 成分和 IL-1β的表达以及分泌的 IL-1β和 sPD-L1 的蛋白水平。本研究结果表明 TQ 具有新型免疫调节作用，强调其不仅作为一种优秀的佐剂，而且作为 HR+和 TNBC 患者的一种潜在免疫治疗药物的可能性。
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