2021 marks the 100th anniversary of the discovery of aerobic glycolysis by German physician Otto Warburg—the Warburg Effect. Warburg discovered that fast-proliferating cancer cells produce energy from glucose in an inefficient manner. Rather than oxidizing the glucose molecule with oxygen inside of mitochondria, cancer cells catabolize it via lactate dehydrogenase (LDH)-mediated fermentation. This oxygen-independent process occurs quickly but leaves much of the energy in glucose untouched. Why these fast-proliferating cells adopt this bioenergetically inefficient way to harvest energy remains a mystery to cancer biologists and immunologists.
Ke Xu, born and raised in Guiyang, China, studied biochemistry and specialized in genetic engineering at McMaster University in Canada prior to joining the Immunology and Microbial Pathogenesis (IMP) program at WCGS in 2013. Xu’s research project in the lab of Dr. Ming Li at Memorial Sloan Kettering Cancer Center focuses on how glucose metabolism regulates T cell immunity in a wide range of stressed conditions such as cancer, bacterial/viral infection and autoimmune disease. “The overall aim of the study is to understand the biological meaning of the famous phenomena, the Warburg Effect in T cells,” says Xu, lead author of a recent publication in Science.
The study, entitled “Glycolysis Fuels Phosphoinositide 3-kinase Signaling to Bolster T cell Immunity,” provides the molecular mechanism that explains why fast-proliferating cells like T cells and cancer cells utilize the Warburg Effect as their major metabolic mean to harvest energy. “By using a conditional genetic knockout mouse model that ablates the A isotype of LDH (LDHA), the key mediator of aerobic glycolysis in activated T cells,” Xu explains, “we are able to elucidate the mechanism of how aerobic glycolysis supports activated CD8+ and CD4+ T cells in the context of infection and autoimmunity model.”
This image shows that the immune activation signal from the T cell receptor (TCR) activates PI3K to promote Warburg Effect by inducing the critical mediator, lactate dehydrogenase (LDHA). In turn, LDHA supports optimal TCR-PI3K signaling through ATP generation from glycolysis, while mitochondrial ATP is irrelevant. LDHA deficiency in T cells resulted in significantly reduced PI3K-Akt-Foxo1 signaling and severely compromised immune response. This positive feedback loop formed between signaling transduction and nutrient metabolism suggests a new model for immune cell regulation.
Xu says his most rewarding experience at WCGS is that he was able to participate in the groundbreaking research and publish his findings in highly prestigious journals. Xu successfully defended his PhD dissertation this month, and seeks to continue his passion for translational research in hopes of developing new therapies and treatments to fight diseases.
