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.
Highlights
Inter- and intra-tumor heterogeneity of breast tumors are a major causal factor for prognostic and drug response disparities
Anti-cancer therapy has proven most effective in combinatorial settings, as tumors can quickly adapt to extrinsic cues
One of the many unanswered questions pertains to the feasibility of targeting tumor cell metabolism without negatively affecting immune cell metabolism in order to enhance immunotherapy response
Summary
Inter- and intra-tumor heterogeneity of breast tumors are a major causal factor for prognostic and drug response disparities. TNBCs are characterized by poor prognosis, early recurrence, and TNBC Metabolic Reprogramming and Immunomodulation increased risk of metastasis, cumulatively accounting for 25% of all breast cancer-related deaths [2]. The lack of hormone receptor expression renders TNBC tumors refractory to the targeted therapeutics currently being implemented for the treatment of hormone receptor positive breast cancer subtypes, essentially limiting treatment options to chemotherapy. TNBC tumors initially respond well to chemotherapy, they develop resistance and display early recurrence rates [3]. The molecular heterogeneity within TNBCs has led to its classification into several intrinsic subtypes, further adding to the predicament of developing personalized approaches to treat TNBCs [4, 5]
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