Naik Adviti, Decock Julie
Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
Front Oncol. 2020 Nov 26;10:598626. doi: 10.3389/fonc.2020.598626. eCollection 2020.
Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. The recent FDA approval for immune checkpoint inhibition in combination with nab-paclitaxel for the treatment of metastatic TNBC created opportunity to advocate for immunotherapy in TNBC patients. However, improving the current low response rates is vital. Most cancers, including TNBC tumors, display metabolic plasticity and undergo reprogramming into highly glycolytic tumors through the Warburg effect. Consequently, accumulation of the metabolic byproduct lactate and extracellular acidification is often observed in several solid tumors, thereby exacerbating tumor cell proliferation, metastasis, and angiogenesis. In this review, we focus on the role of lactate acidosis in the microenvironment of glycolytic breast tumors as a major driver for immune evasion with a special emphasis on TNBCs. In particular, we will discuss the role of lactate regulators such as glucose transporters, lactate dehydrogenases, and lactate transporters in modulating immune functionality and checkpoint expression in numerous immune cell types. This review aims to spark discussion on interventions targeting lactate acidosis in combination with immunotherapy to provide an effective means of improving response to immune checkpoint inhibitors in TNBC, in addition to highlighting challenges that may arise from TNBC tumor heterogeneity.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，与预后不良、早期复发以及缺乏持久的化疗反应和特定靶向治疗相关。美国食品药品监督管理局（FDA）最近批准免疫检查点抑制剂联合白蛋白结合型紫杉醇用于治疗转移性TNBC，这为在TNBC患者中倡导免疫治疗创造了机会。然而，提高目前较低的反应率至关重要。大多数癌症，包括TNBC肿瘤，都表现出代谢可塑性，并通过瓦伯格效应重编程为高度糖酵解的肿瘤。因此，在几种实体瘤中经常观察到代谢副产物乳酸的积累和细胞外酸化，从而加剧肿瘤细胞的增殖、转移和血管生成。在本综述中，我们重点关注乳酸酸中毒在糖酵解性乳腺肿瘤微环境中作为免疫逃逸主要驱动因素的作用，特别强调TNBC。具体而言，我们将讨论乳酸调节剂如葡萄糖转运蛋白、乳酸脱氢酶和乳酸转运蛋白在调节多种免疫细胞类型的免疫功能和检查点表达中的作用。本综述旨在引发关于针对乳酸酸中毒联合免疫治疗的干预措施的讨论，以提供一种有效手段来改善TNBC对免疫检查点抑制剂的反应，此外还强调了TNBC肿瘤异质性可能带来的挑战。
