The immunological Warburg effect: Can a metabolic‐tumor‐stroma score (MeTS) guide cancer immunotherapy?

Abstract

The "glycolytic switch" also known as the "Warburg effect" is a key feature of tumor cells and leads to the accumulation of lactate and protons in the tumor environment.Intriguingly, non-malignant lymphocytes or stromal cells such as tumor-associated macrophages and cancer-associated fibroblasts contribute to the lactate accumulation in the tumor environment, a phenomenon described as the "Reverse Warburg effect." Localized lactic acidosis has a strong immunosuppressive effect and mediates an immune escape of tumors. However, some tumors do not display the Warburg phenotype and either rely on respiration or appear as a mosaic of cells with different metabolic properties. Based on these findings and on the knowledge that T cell infiltration is predictive for patient outcome, we suggest a metabolic-tumor-stroma score to determine the likelihood of a successful anti-tumor immune response: (a) a respiring tumor with high T cell infiltration ("hot"); (b) a reverse Warburg type with respiring tumor cells but glycolytic stromal cells; (c) a mixed type with glycolytic and respiring compartments; and (d) a glycolytic (Warburg) tumor with low T cell infiltration ("cold"). Here, we provide evidence that these types can be independent of the organ of origin, prognostically relevant and might help select the appropriate immunotherapy approach. K E Y W O R D Sacidification, GLUT, immunotherapies, lactate, T cell, Warburg

Immunometabolism: From basic mechanisms to translation

“…[15][16]84 Siska et al focus on the "Warburg effect" which is a key feature of tumor cells and leads to acidification and the accumulation of lactate in the tumor microenvironment. 85 As Both systemic and local influences can also affect metabolism and anti-tumor immunity.…”

“…Critically, treatments such as checkpoint blockade therapies act in part through relieving this metabolic inhibition 15‐16,84 . Siska et al focus on the “Warburg effect” which is a key feature of tumor cells and leads to acidification and the accumulation of lactate in the tumor microenvironment 85 . As a consequence of localized lactic acidosis, immune cell populations within the tumor microenvironment exert an immunosuppressive effect and mediate an effective immune escape by tumor cells.…”

Tumor Lactic Acidosis: Protecting Tumor by Inhibiting Cytotoxic Activity Through Motility Arrest and Bioenergetic Silencing

“…Blocking tumor metabolites pharmacologically is also an exciting approach that might help to prevent inhibition of adoptively transferred T cells and rescue the endogenous immune response against tumor cells. Alterations of the tumor milieu to produce less lactate and acidosis, or conditions that buffer acidity are investigated and show recovery of immune cell function as well as improved therapeutic effects of anti-PD-1 treatments (40,42,43,58,(62)(63)(64)(65)(66)(67).…”

Lactic Acidosis and Hypoglycemia in a Patient with Gastric Diffuse Large B-Cell Lymphoma due to the Warburg Effect

“…The association between type B lactic acidosis and malignancy is known as the Warburg effect [1, 2]. Warburg hypothesized that under aerobic conditions, tumor tissue metabolizes more glucose to lactose than does normal tissue.…”

“…The association between type B lactic acidosis and malignancy is known as the Warburg effect [1, 2]. The Warburg effect is a pathological condition in which cancer cells metabolize glucose to lactic acid under aerobic conditions and produce energy dependent on glycolysis, resulting in combined lactic acidosis and hypoglycemia [1, 2]. Malignant tumors are rarely associated with lactic acidosis, which is rapidly progressive and fatal if not promptly recognized and treated [3].…”