Metabolic Implications of Immune Checkpoint Proteins in Cancer

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.

PD-L1 activity is associated with partial EMT and metabolic reprogramming in carcinomas

“…A primary reason for this is immunosuppression can be competition in TME brought on by increased glucose demand of cancer cells. Consistently, a study reported that specifically targeting PD-L1 with monoclonal antibodies resulted in decreased glycolysis in tumor cells via obstruction of PI3K/Akt/ mTOR pathway and the translation of glycolytic enzymes, thereby improving the anti-tumor function of T cells [58]. These results reinforce our meta-analysis observations that PD-L1 expression and activity levels are positively correlated with glycolysis pathway in bulk microarray and RNA sequencing datasets, with cancer-specific differences shaping the trends in TCGA cohort and single-cell analysis.…”

“…Moreover, when compared to normal tissues, tumor tissues express PD-L1 at considerably higher levels, which drove an interest in inhibiting the PD-L1/PD-1 signaling axis, as an appealing strategy for cancer immunotherapy [55–57]. However, increasing occurrences of resistance in such immunotherapy-based treatments have been reported [58]. It is thus essential to understand the underlying mechanisms behind adaptive immune evasion and its regulation by other molecular factors in the tumor microenvironment (TME) to improve the efficacy of immune checkpoint blockade therapy.…”

Significant metabolic alterations in non-small cell lung cancer patients by epidermal growth factor receptor-targeted therapy and PD-1/PD-L1 immunotherapy

“…However, there is increasing evidence that immune checkpoint inhibitors can affect the metabolic fitness of tumor and T cells. For example, the expression of PD-L1 and B7-H3 (also known as CD276) in tumor cells can stimulate aerobic glycolysis in tumor cells by activating the PI3K/AKT/mTOR pathway ( Li et al, 2019a ; Stirling et al, 2022 ). Conversely, the interaction of PD-1 with PD-L1 or PD-L2 can impair the metabolic reprogramming of T cells by inhibiting the similar pathway ( Wang et al, 2022 ).…”

Immune Cell Metabolic Fitness for Life

“…Interestingly, this approach also influences bioenergetics. In a progressive sarcoma-like tumor microenvironment, for example, the tumor out competes the invading T cells for glucose [ 37 , 68 ]. Many tumors have a high reliance on glycolysis, and therefore require ample glucose.…”

“…Previous research unequivocally demonstrates a link between metabolic phenotype and immune cell fate [ 15 , 61 , 71 , 72 , 73 ], and evidence continues to arise linking T cell metabolic poise to significant anti-tumor behavior [ 14 , 74 ]. In fact, therapies designed to influence T cell fate, such as α-PD1 and α-CTLA-4, significantly impact bioenergetics, shifting T cells to mitochondrial dependence, albeit through different mechanisms [ 44 , 68 , 75 , 76 ]. Altogether, these findings provide a framework for current and future immuno-oncologists to design strategies incorporating metabolic manipulation into the design of CAR T cells.…”