基质MAOB通过抑制抗肿瘤免疫促进前列腺癌生长

Background: Stromal fibroblasts are a key component and regulator of the tumor microenvironment (TME), influencing tumor growth and shaping immune responses. Although stromal-epithelial interactions are known to drive prostate tumor development and progression, the specific stromal factors that modulate the tumor immune milieu in prostate cancer, a notoriously immune-cold malignancy, remain poorly understood. In this study, we investigate the role, mechanism, and therapeutic potential of monoamine oxidase B (MAOB), a mitochondrial enzyme that catalyzes the oxidative deamination of monoamines, in regulating prostate tumor immunity and growth. Methods: The prostatic stromal fibroblasts from Maob knockout (KO) or wild-type (WT) male mice were isolated and co-inoculated with RM-1 mouse prostate cancer cells as subcutaneous implants in immunocompetent C57BL/6 or immunodeficient NSG male mice. Orthotopic RM-1 tumors were also established in the prostates of Maob-KO or WT mice. Tumor growth was monitored, and tumor-infiltrating immune cell profiles were analyzed using flow cytometry. Cytokine and chemokine secretion by Maob-KO and WT stromal fibroblasts was measured with antibody arrays. Results: Stromal Maob deficiency markedly suppressed the growth of co-inoculated RM1 tumors in immunocompetent C57BL/6 mice, while it had only a marginal effect on RM1 tumor growth in immunodeficient NSG mice, indicating a tumor immune response triggered by stromal Maob. RM1 tumors grown in the prostates of Maob-KO mice also appeared notably smaller compared to those in WT mice. Both subcutaneous and orthotopic tumors with Maob-KO stroma exhibited increased infiltration of total and CD8⁺ T cells, along with fewer myeloid-derived suppressor cells, M2 macrophages, and T regulatory cells. In orthotopic tumors, T-cell activity was further elevated in stromal Maob-ablated tumors, as evidenced by higher numbers of Ifngamma and Gzmb-expressing cells. Mechanistically, Maob-KO stromal fibroblasts secrete lower levels of Il-6, Ccl5, Ccl11, and Cxcl12 compared to WT counterparts, which are known to create an immunosuppressive TME. Conclusion: Our findings identify MAOB as a potential stromal mediator of immune evasion in prostate cancer and a stromal-focused therapeutic target to enhance prostate cancer immunotherapies. Funding Acknowledgements: This work was supported by NIH/NCI grants R01CA258634, R37CA233658, and R01CA279528 to BJW.