Researchers discovered that SPD levels decline with age, leading to impaired mitochondrial function and reduced fatty acid oxidation (FAO) in CD8+ T cells, which are critical for tumor immunity. SPD supplementation improved mitochondrial activity, T cell functionality, and responsiveness to PD-1 blockade therapy in aged mice. These findings suggest SPD as a promising intervention for addressing age-related immune decline and resistance to immunotherapy.
In mammals, the immune system's strength declines with age due to various factors, including reduced output and diversity of T-cell antigen repertoires caused by thymic atrophy, metabolic changes induced by inflammation, and defects in the proliferation, differentiation, or survival of T cells. Elderly individuals often suffer from severe infections and cancer, with therapies—such as PD-1 blockade in cancer immunotherapy—showing diminished efficacy compared to younger patients.
Spermidine (SPD), a polyamine that decreases with age, has been shown to improve or delay several age-related diseases, including those affecting the immune system. Proposed mechanisms for rejuvenating the immune system with SPD include enhanced autophagy, translational activity, and mitochondrial metabolism. SPD supplementation has previously been demonstrated to improve antitumor immune responses in animal models. However, the relationship between SPD deficiency and T-cell immunosuppression associated with aging remains largely unknown.
Given the critical role of CD8+ T cells in tumor immunity, researchers from Kyoto University, Tohoku University, and RIKEN in Yokohama, Japan, investigated how aging affects the metabolic and functional characteristics of CD8+ T cells. They explored whether SPD deficiency contributes to the unresponsiveness of aged mice to PD-1 antibody treatment. Additionally, they characterized the changes in CD8+ T cell populations induced by SPD supplementation and identified the molecular mechanisms underlying SPD's effects. Their findings were published in Science on October 28, 2022, under the title The mechanism of acentrosomal spindle assembly in human oocytes.
The researchers discovered that the total concentration and intracellular free concentration of SPD in aged mouse CD8+ T cells were approximately half those in young mice. Metabolically, aged CD8+ T cells exhibited impaired mitochondrial activity compared to younger counterparts, with lower oxygen consumption rates, ATP production, and fatty acid oxidation (FAO) activity.
SPD supplementation was found to enhance the antitumor efficacy of PD-1 blockade immunotherapy in aged mice. Moreover, SPD supplementation was effective in young mice whose tumors were unresponsive to single-agent anti-PD-L1 antibody therapy. Combined SPD and anti-PD-L1 antibody treatment promoted CD8+ T cell proliferation, cytokine production, and mitochondrial ATP generation in vivo. In vitro, SPD enhanced mitochondrial function and metabolized palmitic acid into tricarboxylic acid cycle components within an hour, suggesting a direct interaction between SPD and mitochondrial proteins.
Biochemical analysis identified mitochondrial trifunctional protein (MTP)—a core enzyme in fatty acid β-oxidation—as a binding partner for SPD. MTP, composed of α and β subunits, binds to SPD with high affinity [binding affinity (dissociation constant, Kd) = 0.1 µM] and allosterically enhances its enzymatic fatty acid oxidation activity.
Interestingly, the researchers found that spermine, another polyamine derived from SPD with important cytoprotective functions, also binds MTP and competitively inhibits SPD’s fatty acid oxidation activity. This suggests that the balance between SPD and spermine is critical in determining fatty acid oxidation activity in aged cells. Specific deletion of the MTP α-subunit in T cells abrogated SPD’s enhancement of PD-1 blockade immunotherapy, indicating that MTP is essential for SPD-dependent T cell activation.
In summary, SPD enhances fatty acid oxidation by directly binding to and activating MTP. SPD supplementation boosts fatty acid oxidation activity, improves mitochondrial function, and enhances the cytotoxic functionality of CD8+ T cells. This novel understanding of SPD's properties may aid in developing strategies to prevent and mitigate age-related immune disorders and overcome resistance to PD-1 blockade therapies in cancer, regardless of patient age.