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FK228 reshapes tumor microenvironment to enhance anti-PD-L1 efficacy
Liang Gong1,2, Lu Tian1,3, He Li2,3
1College of Synthetic Biology Industry, Center for Cell and Gene Therapy Research, Hunan University of Arts and Science, Changde, Hunan, China.
Abstract:
The lack of a favorable tumor immune microenvironment (TIME) results in limited response rates to immune checkpoint blockade (ICB) across human solid tumors, necessitating the development of novel combination strategies. In this study, we repurposed FK228, an US FDA-approved histone deacetylase inhibitor that is used clinically in non-solid tumor treatment, as a novel ICB sensitizer in solid tumors and revealed the diverse regulatory functions of FK228 in the TIME. FK228 serves as a novel necroptosis inducer in cancer cells by triggering endoplasmic reticulum stress. This in turn enhances the immunogenicity of cancer cells and increases the infiltration of tumor-killing immunocytes, including CD8+ T and natural killer cells, particularly activating tumor-infiltrated CD8+ T cells. Meanwhile, FK228 treatment shifts macrophages toward the pro-inflammatory phenotype. Moreover, the combined use of FK228 and a PD-L1 inhibitor significantly delay tumor growth and extend the survival of tumor bearing mice. Overall, our findings reveal new possibilities for the clinical application of FK228 in solid tumors and underscore the critical role of histone deacetylases in maintaining the immune-unfavorable TIME.
Insights
FK228, a histone deacetylase inhibitor, enhances anti-cancer immunity by inducing necroptosis and reprogramming the tumor immune microenvironment (TIME). Combining FK228 with PD-L1 blockade effectively delays tumor growth and improves survival in mice.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Limited response to immune checkpoint blockade (ICB) in solid tumors is linked to an unfavorable tumor immune microenvironment (TIME).
- Novel strategies are needed to enhance ICB efficacy in solid tumors.
Purpose of the Study:
- To investigate the potential of FK228, a histone deacetylase inhibitor, as an ICB sensitizer in solid tumors.
- To elucidate the mechanisms by which FK228 modulates the TIME.
Main Methods:
- FK228 was evaluated for its ability to induce necroptosis and endoplasmic reticulum stress in cancer cells.
- Effects of FK228 on immune cell infiltration and phenotype (CD8+ T cells, NK cells, macrophages) within the TIME were assessed.
- Combination therapy with FK228 and a PD-L1 inhibitor was tested in a murine tumor model.
Main Results:
- FK228 acts as a necroptosis inducer by triggering endoplasmic reticulum stress, enhancing cancer cell immunogenicity.
- FK228 increased the infiltration and activation of tumor-killing immune cells, including CD8+ T cells and NK cells.
- FK228 treatment promoted a pro-inflammatory macrophage phenotype and, when combined with PD-L1 blockade, significantly delayed tumor growth and extended survival in mice.
Conclusions:
- FK228 demonstrates potential as a novel sensitizer for immune checkpoint blockade in solid tumors.
- Histone deacetylase inhibition plays a critical role in overcoming immune-suppressive TIME.
- Repurposing FK228 offers new therapeutic possibilities for solid tumor treatment.
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