Lactate Metabolism and Immune Modulation in Breast Cancer: A Focused Review on Triple Negative Breast Tumors

Abstract

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.

Keywords: Warburg effect; anti-tumor immunity; immunosuppression; immunotherapy; lactate acidosis; metabolic reprogramming; triple negative breast cancer; tumor metabolism.

Figure 1

Metabolic phenotypes observed in triple negative breast cancer (TNBC). According to the classic Warburg theory, glycolytic TNBC cells expressing high levels of the lactate transporter MCT4 export lactate, which is taken up by MCT1-expressing stromal cells to generate energy through oxidative phosphorylation (OXPHOS). Alternatively, MCT4 expressing glycolytic stromal cells can export lactate that is used by oxidative tumor cells in a phenomenon called the reverse Warburg effect. The mixed model represents metabolic symbiosis in heterogeneous tumors whereby glycolytic tumor and stromal cells generate lactate to feed oxidative tumor cells. Lastly, the hybrid model depicts metabolic plasticity in TNBC tumor cells that can switch between a glycolytic and oxidative phenotype based on extrinsic cues and glucose availability in the tumor microenvironment (TME).

Figure 2

Strategies to target lactate biogenesis and acidosis to enhance immunotherapy response in triple negative breast cancer (TNBC). TNBC tumor cells display enhanced rates of glycolysis. This metabolic phenotype is supported by the increased expression of glucose transporters (GLUTs) that import glucose into the cell, and of lactate dehydrogenase A (LDHA) that converts the glycolytic intermediate pyruvate into lactate. The augmented production of lactate in TNBC tumors is also associated with higher expression of monocarboxylate transporters (MCTs), which shuttle lactate coupled to protons (H⁺) out of the tumor cell resulting in excessive levels of lactic acid in the tumor microenvironment (TME) and reduced pH. Lactate acidosis in the TME creates an immunosuppressive milieu, which can antagonize the efficacy of immunotherapy. Thus, anti-metabolic strategies could alleviate lactic acid-induced immunosuppression and potentiate immunotherapy such as Adoptive T cell therapy (ACT), Chimeric Antigen Receptor T cell (CAR-T) therapy, and Immune Checkpoint Blockade (ICB), thereby synergistically inhibiting tumorigenesis. Potential strategies to abrogate lactate biogenesis and acidosis include specific targeting of GLUTs, LDHA, MCTs, and the lactate-receptor GPR81 with small molecule inhibitors, inhibition of glucose-pyruvate conversion, systemically lowering the availability of glucose by treatment with biguanides, and buffering the intra-tumoral pH with bicarbonate therapy or proton pump inhibitors (PPIs).