Facts and Perspectives: Implications of tumor glycolysis on immunotherapy response in triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) is an aggressive disease that is difficult to treat and portends a poor prognosis in many patients. Recent efforts to implement immune checkpoint inhibitors into the treatment landscape of TNBC have led to improved outcomes in a subset of patients both in the early stage and metastatic settings. However, a large portion of patients with TNBC remain resistant to immune checkpoint inhibitors and have limited treatment options beyond cytotoxic chemotherapy. The interplay between the anti-tumor immune response and tumor metabolism contributes to immunotherapy response in the preclinical setting, and likely in the clinical setting as well. Specifically, tumor glycolysis and lactate production influence the tumor immune microenvironment through creation of metabolic competition with infiltrating immune cells, which impacts response to immune checkpoint blockade. In this review, we will focus on how glucose metabolism within TNBC tumors influences the response to immune checkpoint blockade and potential ways of harnessing this information to improve clinical outcomes.

Keywords: immune checkpoint inhibitor (ICI); immune microenviroment; regulatory T (Treg) cell; triple negative breast cancer (TNBC); tumor glycolysis.

Figure 1

Relationship between tumor glycolysis, glucose abundance, and T cell response. (A): In glycolysis-high tumors such as TNBC, cancer cells take up a large amount of glucose from the extracellular space to fuel their upregulated glycolytic state. The increase in glycolysis generates a large pool of lactate that is excreted from the cancer cell leading to a hostile, acidic, and nutrient deprived TME. Due to the increased glucose uptake by cancer cells, there is a paucity of glucose remaining in the TME for utilization by T cells that infiltrate the tumor. These nutrient deprived infiltrating T cells are unable to upregulate glycolysis as effectively which results in stunted proliferation and impaired cytotoxic potential. (B): In glycolysis-low tumors, the cancer cells do not rely heavily on glycolysis for energy metabolism, and their uptake of glucose from the extracellular space is minimal. As a result, there is a higher abundance of glucose and a lower abundance of lactate within the TME, leading to a nutrient rich microenvironment, whereby infiltrating T cells can freely take up glucose for their energy needs. Metabolic reprogramming of these T cells favors glycolysis, and contributes to an enhanced effector T cell response. Figure created in BioRender.com.

Figure 2

The interplay between tumor glycolysis, the immune microenvironment, and hypoxia. In highly glycolytic TNBC tumors, glucose is rapidly depleted from the microenvironment and lactate is abundantly produced through glycolysis and released into the extracellular microenvironment, leading to an increase in acidity. Lactate also activates HIF-1a which in turn further promotes glucose metabolism through glycolysis, by upregulating HK and PDK1, and induces VEGF production for neo-vessel formation and metastasis dissemination. Preclinical studies suggest that this lactate-rich, glucose-low, and hypoxic environment leads to exclusion of Teff from the TME and favors Treg retention and phenotypic integrity. Overall, these effects reinforce an immunosuppressed microenvironment, which in turn leads to suboptimal responses to ICIs. Figure created in BioRender.com.