5-Aminolevulinic acid/sodium ferrous citrate enhanced the antitumor effects of programmed cell death-ligand 1 blockade by regulation of exhausted T cell metabolism in a melanoma model.
Cancer Sci
; 112(7): 2652-2663, 2021 Jul.
Article
em En
| MEDLINE
| ID: mdl-33934440
ABSTRACT
Mitochondria are key cytoplasmic organelles. Their activation is critical for the generation of T cell proliferation and cytotoxicity. Exhausted tumor-infiltrating T cells show a decreased mitochondrial function and mass. 5-Aminolevulinic acid (5-ALA), a natural amino acid that is only produced in the mitochondria, has been shown to influence metabolic functions. We hypothesized that 5-ALA with sodium ferrous citrate (SFC) might provide metabolic support for tumor-infiltrating T cells. In a mouse melanoma model, we found that 5-ALA/SFC with a programmed cell death-ligand 1 (PD-L1) blocking Ab synergized tumor regression. After treatment with 5-ALA/SFC and anti-PD-L1 Ab, tumor infiltrating lymphocytes (TILs) were not only competent for the production of cytolytic particles and cytokines (granzyme B, interleukin-2, and γ-interferon) but also showed enhanced Ki-67 activity (a proliferation marker). The number of activated T cells (PD-1+ Tim-3- ) was also significantly increased. Furthermore, we found that 5-ALA/SFC activated the mitochondrial functions, including the oxygen consumption rate, ATP level, and complex V expression. The mRNA levels of Nrf-2, HO-1, Sirt-1, and PGC-1α and the protein levels of Sirt-1 were upregulated by treatment with 5-ALA/SFC. Taken together, our findings revealed that 5-ALA/SFC could be a key metabolic regulator in exhausted T cell metabolism and suggested that 5-ALA/SFC might synergize with anti-PD-1/PD-L1 therapy to boost the intratumoral efficacy of tumor-specific T cells. Our study not only revealed a new aspect of immune metabolism, but also paved the way to develop a strategy for combined anti-PD-1/PD-L1 cancer immunotherapy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Ferrosos
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Ativação Linfocitária
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Linfócitos do Interstício Tumoral
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Ácido Cítrico
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Antígeno B7-H1
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Ácido Aminolevulínico
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Mitocôndrias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cancer Sci
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão