Immune metabolism in PD-1 blockade-based cancer immunotherapy

Abstract

<jats:title>Abstract</jats:title> <jats:p>Energy metabolism plays an important role in proliferating cells. Recent reports indicate that metabolic regulation or metabolic products can control immune cell differentiation, fate and reactions. Cancer immunotherapy based on blockade of programmed cell death protein 1 (PD-1) has been used worldwide, but a significant fraction of patients remain unresponsive. Therefore, clarifying the mechanisms and overcoming patient unresponsiveness are urgent issues. Because cancer immunity consists of interactions between the cancer and host immune cells, there has recently been a focus on the metabolic interactions and/or competition between the tumor and the immune system to address the issue of the unresponsiveness of some patients. Cancer cells render their microenvironment immunosuppressive, driving T cell dysfunction or exhaustion, which is advantageous for cancer cell survival. However, accumulating mechanistic evidence of T cell and cancer cell metabolism has gradually revealed that controlling the metabolic pathways of either type of cell can overcome T cell dysfunction and reprogram the metabolic balance in the tumor microenvironment. Here, we summarize the role of immune metabolism in T cell-based immune surveillance and cancer immune escape. This new concept has boosted the development of combination therapy and predictive biomarkers of immune checkpoint inhibitors.</jats:p>

TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism

“…At the same time, the energy utilization of immune function cells is impaired ( 31 ). In the tumor microenvironment, different metabolic patterns and nutrient-sensing mechanisms jointly regulate the response of immune cells to nutrients ( 32 ). Moreover, negative immune checkpoint molecules are often used by tumor cells to evade immune surveillance.…”

The Epithelial–Mesenchymal Transition Influences the Resistance of Oral Squamous Cell Carcinoma to Monoclonal Antibodies via Its Effect on Energy Homeostasis and the Tumor Microenvironment

“…Although pembrolizumab and nivolumab can both interact with PD-1 to activate T cells, higher energy consumption by CD8+ T cells and a lower concentration of energy substrates in the TME increase the anabolism of T cells; this mainly depends on the activation of the mTORC1 pathway. Increased p38 and ROS accumulation further damages the mitochondria in T cells, leading to an exhausted state [ 58 ]. The PD-1 blockade ultimately shortens the life span of T cells.…”

“…A few patients initially responded to PD-1 blockade therapy but later became unresponsive, possibly due to insufficient effector T cells [ 58 ]. In another study, patients were unresponsive from the start of the treatment [ 59 ].…”

“…Accordingly, we hypothesized that the upregulation of PD-L1 is correlated with cell energy metabolism (regulated by mTORC1) in the up and downstream pathways. Kumar et al [ 58 ] suggested that enhanced activity in the mitochondrial metabolic pathway of CD8+ T cells may affect the PD-1 blockade. Therefore, it may be useful to explore ways to improve the precision of the mitochondrial function of CD8+ T-cells.…”

“…The AMPK pathway prompts cell autophagy and regulates catabolic metabolism and oxidative phosphorylation (OXPHOS) under restricted nutrient and energy conditions. The mTOCR1 pathway preferentially activates anabolic metabolism and glycolysis, while suppressing cell apoptosis [ 58 ].…”