Immune metabolism in PD-1 blockade-based cancer immunotherapy

Abstract

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 the 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 these issues. 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 in cancer immunotherapy with immune checkpoint inhibitors.

Keywords: biomarker; combination therapy; energy metabolism; immune checkpoint; mitochondria.

Fig. 1.

Different mechanisms of tumor-induced immune suppression. Schematic diagrams of different immune escape mechanisms utilized by tumors are shown. There are two main mechanisms: factors that are directly derived from the tumor and bystander tumor-related factors. Lag3, lymphocyte activation gene 3; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domains; VISTA, V-domain immunoglobulin suppressor of T-cell activation.

Fig. 2.

Metabolic competition by cancer cells induces immune suppression and T-cell exhaustion.

Fig. 3.

Distinct metabolic states of naive, effector and memory T cells. Effector T cells are highly metabolic by both the glycolysis and OXPHOS/FAO pathways to meet the high energy demands, with preferential dependence on glycolysis. Memory T cells have an energetically low state and rely on the AMPK-mediated catabolic and OXPHOS/FAO pathways.

Fig. 4.

Combination therapy with metabolic regulators enhances the function and longevity of T cells by up-regulating FAO and OXPHOS during PD-1 blockade. (I) CD8⁺ T cells with PD-1 engagement rely on less glycolysis and more FAO/OXPHOS. (II) PD-1 blockade monotherapy causes a shift towards a glycolytic profile, leading to terminal differentiation. (III) PD-1 blockade combination therapy with bezafibrate (a pan-PPAR agonist) skews OXPHOS/FAO with Bcl2 up-regulation, leading to maintained longevity and functionality.