Manipulation of Glucose Availability to Boost Cancer Immunotherapies

Abstract

The orchestration of T cell responses is intimately linked to the execution of metabolic processes, both in homeostasis and disease. In cancer tissues, metabolic alterations that characterize malignant transformation profoundly affect the composition of the immune microenvironment and the accomplishment of an effective anti-tumor response. The growing understanding of the metabolic regulation of immune cell function has shed light on the possibility to manipulate metabolic pathways as a strategy to improve T cell function in cancer. Among others, glucose metabolism through the glycolytic pathway is central in shaping T cell responses and emerges as an ideal target to improve cancer immunotherapy. However, metabolic manipulation requires a deep level of control over side-effects and development of biomarkers of response. Here, we summarize the metabolic control of T cell function and focus on the implications of metabolic manipulation for the design of immunotherapeutic strategies. Integrating our understanding of T cell function and metabolism will hopefully foster the forthcoming development of more effective immunotherapeutic strategies.

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

“…To date, despite its upregulation, anti-GLUT1 antibodies in the sera of cancer patients were not detected. Among immune cells, a higher expression of GLUT1 was detected in activated T regulatory cells (Tregs) in the TME [ 27 ]. In Tregs, a substantial proportion of glucose is converted into pyruvate for mitochondrial oxidization [ 130 ], and glucose depletion is unfavorable for Treg proliferation [ 27 ].…”

“…Among immune cells, a higher expression of GLUT1 was detected in activated T regulatory cells (Tregs) in the TME [ 27 ]. In Tregs, a substantial proportion of glucose is converted into pyruvate for mitochondrial oxidization [ 130 ], and glucose depletion is unfavorable for Treg proliferation [ 27 ]. GLUT1 expression was also found to be correlated with the density of PD1 + tumor infiltrating lymphocytes (TILs) in specimens from PDA patients [ 18 ].…”

“…In fact, HIF-1α avoided glucose-derived pyruvate from mitochondrial activation promoting glycolysis, which was associated with a reduced suppressive function [ 203 ]. Glycolytic activity modulated FOXP3 expression which regulated Tregs stability [ 27 ]. In a glycolytic environment, ENO1 was directed towards the cytoplasm, avoiding binding with FOXP3 in the nucleus, thus preventing the Tregs suppressive phenotype [ 27 ].…”

“…Glycolytic activity modulated FOXP3 expression which regulated Tregs stability [ 27 ]. In a glycolytic environment, ENO1 was directed towards the cytoplasm, avoiding binding with FOXP3 in the nucleus, thus preventing the Tregs suppressive phenotype [ 27 ]. In addition, silencing ENO1 in induced Tregs (iTregs) led to the reduction in FOXP3 expression as a consequence of lower ENO1 glycolytic activity, demonstrating that suppression of iTregs was mediated by the glycolytic enzyme ENO1 [ 203 ].…”

“…In addition, silencing ENO1 in induced Tregs (iTregs) led to the reduction in FOXP3 expression as a consequence of lower ENO1 glycolytic activity, demonstrating that suppression of iTregs was mediated by the glycolytic enzyme ENO1 [ 203 ]. In the PDA glycolytic context, overexpression of GLUT1 and ENO1 was observed in Tregs, and their activation was due to glucose uptake [ 27 , 92 ].…”