三阴性乳腺癌(TNBC),作为最具侵略性的乳腺癌之一,其特点是预后差,无病生存率和总生存率非常低。近年来,靶向T细胞检查点分子的免疫治疗方法,如细胞毒性淋巴细胞抗原-4(CTLA-4),程序性死亡1(PD-1)或其配体,程序性死亡配体1(PD-L1),已显示出巨大的潜力,并已作为单一疗法或与其他方式结合用于治疗各种癌症。然而,尽管取得了显著进展,TNBC患者对这种方法的反应率低,通常对免疫检查点阻断产生抗性,导致治疗失败。肿瘤微环境中的细胞外酸中毒(也称为Warburg效应)是阻止免疫细胞产生有效反应并导致免疫治疗失败的因素之一。因此,降低肿瘤酸度对于提高癌症免疫疗法的有效性很重要,这在TNBC环境中尚未实现。在这项研究中,口服碳酸氢钠(NaHCO3)增强了抗PD-L1抗体治疗的抗肿瘤作用,正如产生的抗肿瘤免疫力所证明的那样,在4T1-Luc乳腺癌模型中抑制肿瘤生长并提高生存率。这里,我们显示,NaHCO3增加细胞外pH(pHe)在肿瘤组织体内,伴随着T细胞浸润增加的效应,T细胞活化和IFN-γ,IL2和IL12p40mRNA在肿瘤组织中的表达,以及肿瘤引流淋巴结中T细胞活化的增加。有趣的是,这些变化在对NaHCO3+抗PD-L1联合治疗的应答中进一步增强.此外,酸性细胞外条件导致体外PD-L1表达显著增加。一起来看,这些结果表明,碱化治疗作为一种新的肿瘤微环境免疫调节剂具有潜力,我们假设NaHCO3可以增强抗PD-L1乳腺癌治疗的抗肿瘤作用.通过提供强大的个性化医学范例,这些治疗的组合可能对未来的TNBC免疫治疗方法产生特殊影响。因此,我们的研究结果对于改善TNBC患者的预后具有巨大的转化潜力.
Triple-negative breast cancer (TNBC), as one of the most aggressive forms of breast cancer, is characterized by a poor prognosis and a very low rate of disease-free and overall survival. In recent years, immunotherapeutic approaches targeting T cell checkpoint molecules, such as cytotoxic lymphocyte antigen-4 (CTLA-4), programmed death1 (PD-1) or its ligand, programmed death ligand 1 (PD-L1), have shown great potential and have been used to treat various cancers as single therapies or in combination with other modalities. However, despite this remarkable progress, patients with TNBC have shown a low response rate to this approach, commonly developing resistance to immune checkpoint blockade, leading to treatment failure. Extracellular acidosis within the tumor microenvironment (also known as the Warburg effect) is one of the factors preventing immune cells from mounting effective responses and contributing to immunotherapy treatment failure. Therefore, reducing tumor acidity is important for increasing cancer immunotherapy effectiveness and this has yet to be realized in the TNBC environment. In this study, the oral administration of sodium bicarbonate (NaHCO3) enhanced the antitumor effect of anti-PD-L1 antibody treatment, as demonstrated by generated antitumor immunity, tumor growth inhibition and enhanced survival in 4T1-Luc breast cancer model. Here, we show that NaHCO3 increased extracellular pH (pHe) in tumor tissues in vivo, an effect that was accompanied by an increase in T cell infiltration, T cell activation and IFN-γ, IL2 and IL12p40 mRNA expression in tumor tissues, as well as an increase in T cell activation in tumor-draining lymph nodes. Interestingly, these changes were further enhanced in response to combined NaHCO3 + anti-PD-L1 therapy. In addition, the acidic extracellular conditions caused a significant increase in PD-L1 expression in vitro. Taken together, these results indicate that alkalizing therapy holds potential as a new tumor microenvironment immunomodulator and we hypothesize that NaHCO3 can enhance the antitumor effects of anti-PD-L1 breast cancer therapy. The combination of these treatments may have an exceptional impact on future TNBC immunotherapeutic approaches by providing a powerful personalized medicine paradigm. Therefore, our findings have a great translational potential for improving outcomes in TNBC patients.