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

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.

Regulatory T-cells-related signature for identifying a prognostic subtype of hepatocellular carcinoma with an exhausted tumor microenvironment

“…HMOX1 inhibitors enhance the anti-tumor effects of anti-PD-L1 antibodies in mouse melanoma and also reduce tumor size by abolishing resistance to anti-PD1 immunotherapy in female mice bearing E0771 mammary tumors ( 43 ). HMOX1 has also been implicated in PD1-involved exhausted T-cell metabolic regulation in melanoma ( 44 ). The overexpressed receptor tyrosine kinase c-Mett in renal cancer cells can inhibit cancer cell apoptosis by regulating the synergistic effect between HMOX1 and PD-L1 ( 45 ).…”

Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity

“…Exogenous supplementation of amino acid shows a good anti-tumor effect by activating mitochondrial metabolism of T cells, and protects T cells from exhaustion and enhancing T-cell proliferation and activation, such as 5-aminolevulinic acid, N-acetyl cysteine, asparagine, proline, and arginine [103][104][105][106][107]. At present, some drugs targeting amino acid metabolism have been developed for anti-tumor treatment.…”

Safety and immune-supportive potential of the food supplement 5-aminolevulinic acid phosphate for patients with COVID-19: An open-label, non-randomized pilot study

“…The immunologically supportive properties of 5-ALA with SFC are attributed to the fact that it strengthens the mitochondrial function of T cells [20]. Patients with COVID-19 have reduced T cell concentrations [21].…”