In:
Science, American Association for the Advancement of Science (AAAS), Vol. 378, No. 6618 ( 2022-10-28)
Abstract:
In mammals, the power of the immune system decreases with age. This is because of multiple factors, including a decrease in the output and diversity of the antigenic repertoire of T cells caused by thymus involution; changes in the cellular metabolism caused by inflammation; and defective proliferative, differentiation, or survival capacities of the immune cells. Aged individuals frequently suffer from severe infections and cancers, and often the therapies applied, including programmed cell death protein 1 (PD-1) blockade in cancer immunotherapy, are ineffective when compared with results in young patients. A biogenic polyamine, spermidine (SPD), decreases with age, and SPD supplementation was shown to improve or delay several age-related pathologies, including those of the immune system. Among the proposed mechanisms responsible for rejuvenation of the immune system by SPD were enhanced autophagy, translational activity, and mitochondrial metabolism. SPD supplementation has previously been shown to enhance the antitumor immunity in animal models. However, it remains largely unknown how SPD deficiency relates to the T cell immune suppression induced by aging. RATIONALE Because CD8 + T cells are key players in tumor immunity, we investigated how aging would affect the metabolic and functional characteristics of CD8 + T cells. We asked whether SPD insufficiency could be a factor contributing to nonresponsiveness to PD-1 antibody therapy in aged mice. We sought to characterize the CD8 + T cell population changes induced by SPD supplementation in aged mice and to identify the molecular mechanisms for the SPD action. RESULTS We found that the total and free intracellular concentrations of SPD in CD8 + T cells from aged mice were about half as much as the concentrations found in young mice. Bioenergetically, aged CD8 + T cells showed impaired mitochondrial activity with lower oxygen consumption rate, adenosine 5′-triphosphate (ATP) production, and fatty acid oxidation (FAO) activity compared with young CD8 + T cells. We show that SPD supplementation enhanced the antitumor activity of PD-1 blockade immunotherapy in aged mice. SPD supplementation proved to also be effective in young mice with tumors unresponsive to single anti–programmed death-ligand 1 (PD-L1) antibody therapy. SPD and anti–PD-L1 antibody combination treatment enhanced the proliferation, cytokine production, and mitochondrial ATP production of CD8 + T cells in vivo. In vitro, SPD effectively enhanced mitochondrial functions and metabolized palmitate into tricarboxylic acid cycle components within 1 hour, which suggests the possibility of direct SPD binding to mitochondria-related proteins. Biochemical analysis identified SPD binding to mitochondrial trifunctional protein (MTP), which is the central enzyme of fatty acid β-oxidation. MTP is composed of α and β subunits, both of which bind SPD. Several assays using the MTP synthesized and purified from Escherichia coli revealed that SPD bound with strong affinity [binding affinity (dissociation constant, K d ) = 0.1 μM] and allosterically enhanced their enzymatic FAO activities. Furthermore, we found that spermine, another polyamine derived from SPD with important cellular protective functions, also directly binds to MTP and competitively inhibits FAO activity of SPD, which suggests the importance of SPD and spermine balance for FAO evaluation in aged cells. T cell–specific deletion of the MTP α subunit abolished enhancement of PD-1 blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation. CONCLUSION SPD enhances FAO by directly binding and activating the MTP. SPD supplementation enhances the FAO activity and boosts the mitochondrial activities and cytotoxic functions of CD8 + T cells. We provide new insights into the properties of SPD that may facilitate the development of strategies to prevent and improve outcomes of age-related immune pathologies and combat unresponsiveness to PD-1 blockade therapy in cancers, regardless of age. SPD binds to MTP and activates FAO in T cells. SPD directly activates MTP, which plays a central role in FAO. SPD concentration is decreased in aged T cells, leading to low FAO activity and ATP production compared with those in young T cells. SPD supplementation activates FAO in aged and young T cells, which enhances the efficacy of PD-1 blockade cancer immunotherapy. CoA, coenzyme A; TCA, tricarboxylic acid; ETC, electron transport chain. [Figure created by Biorender]
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abj3510
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2022
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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