Abstract
Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.
Highlights
Immune checkpoint proteins are targets of significant interest for cancer therapeutics to enhance T cell antitumor function
When PD-1 is ligated on effector T cells, increased expression of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of fatty acid oxidation, and adipose triacylglycerol lipase (ATGL), an enzyme involved in lipolysis, occurs (Figure 1B) [22]
While there are several stimulatory immune checkpoint proteins in this review, we focus on CD28, inducible costimulator (ICOS), glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR), and 4-1BB due to the effects on metabolism and clinical stage of agonist drugs
Summary
Immune checkpoint proteins are targets of significant interest for cancer therapeutics to enhance T cell antitumor function. The metabolic reprogramming associated with immune checkpoint proteins is essential to understand the development of resistance and immune-related adverse events (irAE) It can provide valuable information for potential biomarkers or targeted metabolic therapies combined with immune checkpoint therapies to enhance patient response and survival. PD-1 is often known for its interaction and activation with the ligands PD-L1/PD-L2, while CTLA-4 interacts with the receptor CD80/CD86 (B7-1/B7-2) [11,12,13] The activation of these inhibitory immune checkpoint proteins alters metabolism within T cells, which can impact their phenotype and respective function (Figure 1). This section of the review will focus on the metabolic reprogramming associated with activating inhibitory immune checkpoint proteins on both T cells and other immune cells; and how immune checkpoint blockade therapies potentially regulate cell bioenergetics to enhance antitumor immune responses
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