Lactate, a tumour-cell metabolite, promotes immune evasion via GPR81: A potential novel strategy to boost cancer immunotherapy?
Tumour cells generate lactate as a signaling molecule to aid in growth and metastasis. We have uncovered a novel function for this metabolite; it blunts the ability of the body’s immune system to recognize and kill tumour cells, thus making it possible for the cancer to evade immune attack.
Timothy P. Brown and Vadivel Ganapathy
One of the hallmarks of tumour-cell metabolism is the generation of lactate, not only from glucose via aerobic glycolysis, known as Warburg phenomenon, but also from glutamine via glutaminolysis. Lactate is effectively released from cancer cells lest accumulation of the metabolite will lead to intracellular acidification with detrimental consequences. In recent years, it has become increasingly recognized that this tumour-cell metabolite is actually a signaling molecule with its own cell-surface receptor, known as GPR81. Activation of this receptor by extracellular lactate elicits multiple biological effects that promote tumour cell growth and proliferation. This includes angiogenesis, DNA repair, chemoresistance, and induction of surface molecules leading to cell death by cytotoxic T cells. But all the functions of lactate known thus far involve GPR81 expressed on tumour cells, the primary cells that also generate and release lactate as the agonist to activate the receptor. Indeed, GPR81 receptor expression is upregulated in tumour cells, and the tumour microenvironment contains high levels of its agonist lactate, all designed to promote tumour growth and metastasis. These actions of lactate are autocrine in nature.
Our studies have uncovered a paracrine function for this tumour-cell metabolite, which also promotes tumour growth, but via a hitherto unknown pathway. Lactate, released into the microenvironment by the tumour cells, acts on immune cells to interfere with their normal ability to identify the tumour cells as foreign and kill them. As tumour cells are aberrant cells and express new antigenic epitopes on their cell surface not found on normal cells, the immune system is designed to recognize these tumour cells and eradicate them; a phenomenon known as immune surveillance. This has multiple steps, one of them being the role of antigen-presenting dendritic cells that process tumour-cell proteins and present the neoantigens on their cell surface via the major histocompatibility complex II molecules (MHC II). The new tumour cell-specific antigenic epitopes are to be recognized by other immune cells to initiate a subsequent cascade of events, ultimately leading to the killing of other surviving tumour cells. But if this strategy is one-hundred percent successful, we will never get cancer. Tumour cells must find ways to evade this immune surveillance and survive the immune attack in order to grow and spread successfully. Our studies show that the tumour-cell metabolite lactate helps to accomplish this goal. Lactate acts on its receptor expressed on antigen-presenting dendritic cells and suppress the expression of MHC II on their cell surface, thus interfering with the ability of these cells to present tumour cell-specific antigens to adaptive immune cells. This is a logically simple, but very effective, strategy employed by tumour cells to evade an immune attack. Our studies thus uncover a novel paracrine pathway for the tumour-cell metabolite lactate to promote cancer growth.
Cancer immunotherapy is the latest addition to the armamentarium in our fight against cancer. The basis of this therapeutic approach is to find a way to counteract the tumour cell’s ability to evade the immune system. This approach has proved to be successful to a significant extent but could be made even more powerful to improve its efficacy in eradicating cancer. Based on our studies, we predict that interference with the actions of lactate on the antigen-presenting cells that facilitate a tumour cell’s ability to evade the immune attack would potentiate the efficacy of currently available immunotherapy strategies. In theory, this could be achieved by antagonizing the lactate-induced GPR81 signaling. There are no GPR81 antagonists reported in the literature, but our studies suggest that such antagonists would be potentially useful as novel drugs for cancer treatment, either as a single agent or in combination with other chemo/immunotherapeutic agents.