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TBX21 facilitates the progression of prostate cancer by modulating the immunosuppression microenvironment via enhancing the proportion of Treg cells

ABSTRACT: Abstract Background: Prostate cancer (PCa) remains a major health burden, and identifying target molecules will provide new research ideas for treating PCa. TBX21 is a transcriptional factor with critical functions in tumor development, roles of which in PCa were studied herein. Methods: TBX21 expression was evaluated by RNA-seq, RT-PCR, Western blot, and immunohistochemistry in PCa tissues and cell lines. Functional assays were performed using LNCaP and 22RV1 cells with TBX21 knockdown to assess proliferation and apoptosis. Tumor growth and immune alterations were examined in xenograft and humanized immune cell models, while flow cytometry and Western blot were used to characterize immune cell subsets and effector molecules. Results: TBX21 expression was significantly elevated in PCa tissues and cell lines. TBX21 knockdown was associated with reduced proliferation and increased apoptosis in vitro and suppressed tumor growth in vivo. In humanized xenografts, TBX21 silencing was accompanied by a decrease in regulatory T cells (Treg) and an increase in Th17 and cytotoxic CD8⁺ T cells, together with enhanced expression of effector molecules (TNF-α, GZMB). Co-culture experiments showed that TBX21-deficient tumor cells reduced the induction of CD25⁺Foxp3⁺ Treg cells from activated CD4⁺ T cells. Conclusion: TBX21 is associated with tumor progression and an immunosuppressive microenvironment in PCa, underscoring its potential role in modulating the tumor–immune balance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310339 | GEO | 2025/12/04

REPOSITORIES: GEO

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Project description:Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related mortility among men in western societies. PCa exhibits a protracted progression, initiating as Prostatic Intraepithelial Neoplasia (PIN), advancing to adenocarcinoma, and eventually culminating in metastatic dissemination. The advent of Immune Checkpoint Inhibitors (ICI) has been revolutionized the field of cancer immunology. However, the efficacy of immunotherapy in PCa has been limited, and the role of immune cells in prostate tumorigenesis has only recently been explored. In this study, we performed an in-depth characterization of immune cells in healthy murine prostate and during PCa progression in PTEN(i)pe-/- mice. In this model, the PTEN gene is selectively ablated in prostatic luminal epithelial cells at adulthood (PSA-CreERT2), closely mimicking human PCa development. Notably, tumor progression in this model is gradual, with the PIN stage manifesting at 3 months post-gene invalidation and the adenocarcinoma stage at 9 months. The strict temporal control of PTEN depletion coupled with the slow tumor progression, makes the PTEN(i)pe-/- mouse model an invaluable tool for delineating immune infiltration during tumor development and evaluating therapeutic interventions. Here we performed scRNAseq on CD45+ immune cells residing in the dorsolateral lobes of prostate at respectively 3 and 9 months post tamoxifen treatment of PTEN(i)pe-/- and control mice, allowing to establish a high-resolution immune atlas of murine PCa from neoplasia to adenocarcinoma. Our findings reveal significant heterogeneity among mononuclear phagocytes (dendritic cells and macrophages), neutrophils and lymphoid immune cells in the prostate. Various neutrophil clusters exhibit an immunosuppressive signature from the PIN stage onward. We observed the recruitment of Trem2+ tumor-associated macrophage subset during PCa, potentially contributing to tumorigenesis. Additionally, there was an increase in CD8+ T lymphocytes in PCa, which exhibited an activated/exhausted phenotype. Our study elucidates the intricate dynamics of immune cell behavior in PCa from early to late stages. These insights pave the way for novel immunotherapeutic strategies to treat prostate cancer, thereby advancing the field of tumor immunology.

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TBX21 facilitates the progression of prostate cancer by modulating the immunosuppression microenvironment via enhancing the proportion of Treg cells

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