PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation

Abstract

During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated T cells are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty acid β-oxidation (FAO). PD-1 promotes FAO of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty acids. Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated cells. Because T cells utilize glycolysis during differentiation to effectors, our findings reveal a metabolic mechanism responsible for PD-1-mediated blockade of T-effector cell differentiation. The enhancement of FAO provides a mechanistic explanation for the longevity of T cells receiving PD-1 signals in patients with chronic infections and cancer, and for their capacity to be reinvigorated by PD-1 blockade.

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

“…We hypothesized that FAO would be lower in Pdl1 -/-donor T cells because PD-1 ligation of activated T cells can limit glycolysis and amino acid metabolism while increasing FAO (45), and GVHD Teffs are under high metabolic stress and known to utilize FAO to provide energy for their survival and/or function. We first measured FA uptake using BoDipy C1-C12 , a fluorescent FA analog, and found that it was significantly reduced in Pdl1 -/-donor T cells ( Figure 10A).…”

Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade

“…The PD-1/PD-L1 axis is known to mediate peripheral tolerance and attenuation of acute inflammatory responses through modulation of T-cell receptor (TCR) signal transduction, metabolic reprogramming, anergy and apoptosis (16)(17)(18).…”

Cytokines and metabolic factors regulate tumoricidal T-cell function during cancer immunotherapy

“…PD-1 is also expressed on melanoma cells, and its binding to PD-L1 augments glucose uptake and glycolysis through activation of the mTOR signaling pathway [53,67]. Intriguingly, PD-1 ligation on T cells has the opposite effect of blocking glycolysis [68], and thus impeding glycolysis-dependent effector functions [54]. Thus, PD-1/PD-L1 checkpoint blockade not only terminates an inhibitory signal on TIL but also indirectly boosts the activity of these T cells by increasing intratumoral glucose availability as a consequence of limiting glucose consumption by the tumor cells.…”