Enzalutamide, an Androgen Receptor Antagonist, Enhances Myeloid Cell-Mediated Immune Suppression and Tumor
Camila R Consiglio1, Olga Udartseva2, Kimberly D Ramsey2
1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Abstract:
Androgen receptor (AR) antagonism increases overall survival in prostate cancer; however, treatment failure leads to tumor progression and patient mortality. The effect of AR modulation on AR+ nontumor cells that participate in the resistance to AR antagonism is poorly understood. Tumor-infiltrating myeloid cells, including macrophages and myeloid-derived suppressor cells (MDSC), express AR and promote prostate cancer progression. We investigated how AR antagonism affects myeloid cell function and metabolism in an AR-independent murine colon tumor model. Systemic blockade of AR with enzalutamide resulted in increased MC-38 tumor growth in vivo even when AR was knocked out of MC-38 tumor cells. MC-38 tumor growth was also increased when immunocompetent, but not immunodeficient, mice were coinjected with tumor cells and MDSCs treated with enzalutamide or lacking AR, suggesting that AR regulated the ability of MDSCs to suppress adaptive immunity. Myeloid AR-knockout male mice also displayed increased growth of TRAMP C2 prostate tumors when compared with wild type. Inhibition of AR signaling suppressed mitochondrial respiration in myeloid cells via MPC/AMPK signaling pathways; suppression of mitochondrial respiration increased MDSC tumor-promoting functions. Our work showed that AR regulates a tumor-promoting myeloid cell phenotype and influences myeloid cell metabolism. These findings suggest that tumor resistance to AR antagonism is due, in part, to changes in myeloid cell function and metabolism.
Insights
Androgen receptor (AR) antagonism resistance in prostate cancer may stem from myeloid cells. Blocking AR impairs myeloid cell metabolism, enhancing their tumor-promoting functions and immune suppression.
Area of Science:
- Oncology
- Immunology
- Cell Metabolism
Background:
- Androgen receptor (AR) antagonism improves survival in prostate cancer but treatment failure leads to mortality.
- The role of AR in non-tumor cells, particularly myeloid cells, during AR antagonism resistance is not well understood.
- Myeloid cells like macrophages and myeloid-derived suppressor cells (MDSCs) express AR and contribute to prostate cancer progression.
Purpose of the Study:
- To investigate the impact of AR antagonism on myeloid cell function and metabolism.
- To determine if AR signaling in myeloid cells influences tumor growth and immune suppression.
- To elucidate the mechanisms by which AR regulates myeloid cell phenotype and function.
Main Methods:
- Utilized an AR-independent murine colon tumor model (MC-38) and AR-dependent prostate tumor model (TRAMP C2).
- Administered systemic AR blockade with enzalutamide in wild-type and myeloid AR-knockout mice.
- Assessed tumor growth in vivo, coinjected tumor cells with MDSCs, and analyzed myeloid cell mitochondrial respiration and AMPK signaling.
Main Results:
- Systemic AR blockade with enzalutamide increased MC-38 tumor growth, even in AR-deficient tumor cells.
- AR blockade or deficiency in MDSCs enhanced tumor growth in immunocompetent mice, indicating AR regulates MDSC-mediated immune suppression.
- Myeloid AR-knockout mice showed increased TRAMP C2 prostate tumor growth compared to wild-type controls.
- Inhibition of AR signaling suppressed mitochondrial respiration in myeloid cells via MPC/AMPK pathways, enhancing MDSC tumor-promoting functions.
Conclusions:
- AR signaling regulates a tumor-promoting myeloid cell phenotype and influences myeloid cell metabolism.
- Changes in myeloid cell function and metabolism contribute to tumor resistance to AR antagonism.
- Targeting AR in myeloid cells may offer novel therapeutic strategies for overcoming treatment resistance in prostate cancer.
