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 NaHCO3increased 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 NaHCO3can 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.
三阴性乳腺癌作为最具侵袭性的乳腺癌亚型之一，其临床特征表现为预后不良、无病生存率和总生存率极低。近年来，针对T细胞检查点分子的免疫疗法——如细胞毒性淋巴细胞抗原-4、程序性死亡受体1及其配体程序性死亡配体1——已展现出巨大潜力，并作为单一疗法或联合疗法应用于多种癌症治疗。然而尽管取得显著进展，三阴性乳腺癌患者对该疗法的应答率仍然较低，常出现免疫检查点阻断耐药性，最终导致治疗失败。肿瘤微环境中的细胞外酸中毒（即瓦博格效应）是阻碍免疫细胞产生有效应答并导致免疫治疗失败的关键因素之一。因此降低肿瘤酸度对提升癌症免疫治疗效果至关重要，而这在三阴性乳腺癌微环境中尚未实现。本研究通过4T1-Luc乳腺癌模型证实，口服碳酸氢钠可增强抗PD-L1抗体治疗的抗肿瘤效果，具体表现为诱导抗肿瘤免疫、抑制肿瘤生长并延长生存期。实验显示碳酸氢钠能提高体内肿瘤组织的细胞外pH值，同时伴随肿瘤组织中T细胞浸润增加、T细胞活化增强以及IFN-γ、IL2和IL12p40 mRNA表达上调，肿瘤引流淋巴结中的T细胞活化也显著增强。值得注意的是，这些变化在碳酸氢钠联合抗PD-L1治疗中进一步放大。此外体外实验表明酸性细胞外环境会显著提升PD-L1表达水平。综合结果表明，碱化疗法具有成为新型肿瘤微环境免疫调节剂的潜力，我们推测碳酸氢钠能增强抗PD-L1乳腺癌治疗的抗肿瘤效应。这种联合治疗方案通过构建强大的个体化医疗范式，可能对未来三阴性乳腺癌免疫治疗策略产生深远影响。因此本研究对改善三阴性乳腺癌患者预后具有重要的转化医学价值。
肿瘤(癌症)患者之家