論文 - 詳細
| RRC ID | 85687 |
|---|---|
| 著者 | Hu X, Que W, Hirano H, Wang Z, Nozawa N, Ishii T, Ishizuka M, Ito H, Takahashi K, Nakajima M, Tanaka T, Zhu P, Guo WZ, Li XK. |
| タイトル | 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. |
| ジャーナル | Cancer Sci |
| 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. |
| 巻・号 | 112(7) |
| ページ | 2652-2663 |
| 公開日 | 2021-7-1 |
| DOI | 10.1111/cas.14930 |
| PMID | 33934440 |
| PMC | PMC8253271 |
| MeSH | Adenosine Triphosphate / metabolism Aminolevulinic Acid / pharmacology* Animals B7-H1 Antigen / antagonists & inhibitors* Cell Line, Tumor Citric Acid / pharmacology* Combined Modality Therapy Female Ferrous Compounds / pharmacology* Heme Oxygenase-1 / metabolism Hepatitis A Virus Cellular Receptor 2 / metabolism Ki-67 Antigen / metabolism Lymphocyte Activation / drug effects* Lymphocyte Count Lymphocytes, Tumor-Infiltrating / cytology Lymphocytes, Tumor-Infiltrating / drug effects* Lymphocytes, Tumor-Infiltrating / metabolism Melanoma, Experimental / immunology Melanoma, Experimental / metabolism Melanoma, Experimental / pathology Melanoma, Experimental / therapy Membrane Proteins / metabolism Mice Mice, Inbred BALB C Mice, Inbred C57BL Mitochondria / drug effects* Mitochondria / metabolism Nuclear Respiratory Factor 1 / metabolism Oxygen Consumption / drug effects Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism Sirtuin 1 / metabolism |
| IF | 4.966 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | B16/BL6(RCB2638) B16F10(RCB2630) |