Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
Medical Oncology Centre of Rosebank, Johannesburg, South Africa.
Front Immunol. 2022 May 23;13:823842. doi: 10.3389/fimmu.2022.823842. eCollection 2022.
Breast cancer cells exploit the up-regulation or down-regulation of immune checkpoint proteins to evade anti-tumor immune responses. To explore the possible involvement of this mechanism in promoting systemic immunosuppression, the pre-treatment levels of soluble co-inhibitory and co-stimulatory immune checkpoint molecules, as well as those of cytokines, chemokines, and growth factors were measured in 98 newly diagnosed breast cancer patients and compared with those of 45 healthy controls using multiplex bead array and ELISA technologies. Plasma concentrations of the co-stimulatory immune checkpoints, GITR, GITRL, CD27, CD28, CD40, CD80, CD86 and ICOS, as well as the co-inhibitory molecules, PD-L1, CTLA-4 and TIM-3, were all significantly lower in early breast cancer patients compared to healthy controls, as were those of HVEM and sTLR-2, whereas the plasma concentrations of CX3CL1 (fractalkine), CCL5 (RANTES) and those of the growth factors, M-CSF, FGF-21 and GDF-15 were significantly increased. However, when analyzed according to the patients' breast cancer characteristics, these being triple negative breast cancer (TNBC) vs. non-TNBC, tumor size, stage, nodal status and age, no significant differences were detected between the plasma levels of the various immune checkpoint molecules, cytokines, chemokines and growth factors. Additionally, none of these biomarkers correlated with pathological complete response. This study has identified low plasma levels of soluble co-stimulatory and co-inhibitory immune checkpoint molecules in newly diagnosed, non-metastatic breast cancer patients compared to healthy controls, which is a novel finding seemingly consistent with a state of systemic immune dysregulation. Plausible mechanisms include an association with elevated levels of M-CSF and CCL5, implicating the involvement of immune suppressor cells of the M2-macrophage/monocyte phenotype as possible drivers of this state of systemic immune quiescence/dysregulation.
乳腺癌细胞利用免疫检查点蛋白的上调或下调来逃避抗肿瘤免疫反应。为了探讨这种机制在促进全身免疫抑制中的可能作用，我们使用多重珠粒阵列和 ELISA 技术测量了 98 例新诊断的乳腺癌患者和 45 例健康对照者的可溶性共抑制和共刺激免疫检查点分子以及细胞因子、趋化因子和生长因子的预处理水平，并与健康对照者进行了比较。与健康对照组相比，早期乳腺癌患者的共刺激免疫检查点分子 GITR、GITRL、CD27、CD28、CD40、CD80、CD86 和 ICOS，以及共抑制分子 PD-L1、CTLA-4 和 TIM-3 的血浆浓度均显著降低，HVEM 和 sTLR-2 的血浆浓度也显著降低，而 CX3CL1（ fractalkine）、CCL5（RANTES）和生长因子 M-CSF、FGF-21 和 GDF-15 的血浆浓度则显著升高。然而，根据患者的乳腺癌特征进行分析，即三阴性乳腺癌（TNBC）与非 TNBC、肿瘤大小、分期、淋巴结状态和年龄，在各种免疫检查点分子、细胞因子、趋化因子和生长因子的血浆水平之间未检测到显著差异。此外，这些生物标志物均与病理完全缓解无关。本研究发现，与健康对照组相比，新诊断的非转移性乳腺癌患者的可溶性共刺激和共抑制免疫检查点分子的血浆水平较低，这是一种新发现，似乎与全身免疫失调状态一致。可能的机制包括与 M-CSF 和 CCL5 水平升高相关，这表明 M2 巨噬细胞/单核细胞表型的免疫抑制细胞可能是这种全身免疫静止/失调状态的驱动因素。
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