Combined therapy targeting AR and EZH2 curbs castration-resistant prostate cancer enhancing anti-tumor T-cell response.

Aim: Castration-resistant prostate cancer (CRPC) eventually becomes resistant to androgen receptor pathway inhibitors like enzalutamide. Immunotherapy also fails in CRPC. We propose a new approach to simultaneously revert enzalutamide resistance and rewire anti-tumor immunity. Methods: We investigated in vitro and in subcutaneous and spontaneous mouse models the effects of combining enzalutamide and GSK-126, a drug inhibiting the epigenetic modulator EZH2. Results: Enzalutamide and GSK-126 synergized to reduce CRPC growth, also restraining tumor neuroendocrine differentiation. The anti-tumor activity was lost in immunodeficient mice. Indeed, the combination treatment awoke cytotoxic activity and IFN-γ production of tumor-specific CD8+ T lymphocytes. Conclusion: These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer.

Prostate cancer depends on hormones called androgens for its growth. Therefore, hormonal therapies are commonly used. However, the tumor often does not respond to these treatments and new therapeutic approaches are needed. Here, using cell and mouse models, we have tested a new combination between hormone therapy and a drug that restrains an enzyme regulating gene expression. Our results have shown that this combination therapy not only reduces the growth of the tumor but also stops it from becoming more aggressive. This is really important because aggressive prostate cancer is much harder to treat. We have also found that this approach helps the immune system recognizing and attacking cancer cells. More research is needed to identify the mechanism of action of this treatment. However, our findings suggest that this approach could pave the way for new therapeutic strategies, including using immunotherapy, typically unsuccessful in treating prostate cancer.

Intracellular osteopontin promotes the release of TNF by mast cells to restrain neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer that emerges as tumors become resistant to hormone therapies or, rarely, arises de novo in treatment-naïve patients. The urgent need for effective therapies against NEPC is hampered by the limited knowledge of the biology governing this lethal disease. Based on our prior observations in the TRAMP spontaneous prostate cancer model, in which the genetic depletion of either mast cells (MCs) or the matricellular protein osteopontin (OPN) increases NEPC frequency, we tested the hypothesis that MCs can restrain NEPC through OPN production, using in vitro co-cultures between murine or human tumor cell lines and MCs, and in vivo experiments. We unveiled a role for the intracellular isoform of OPN (iOPN), so far neglected compared to the secreted isoform. Mechanistically, we unraveled that iOPN promotes TNF production in MCs via the TLR2/TLR4-MyD88 axis, specifically triggered by the encounter with NEPC cells. We found that MC-derived TNFin turn, hampered the growth of NEPC. We then identified the protein syndecan-1 (SDC1) as the NEPC-specific TLR2/TLR4 ligand that triggered this pathway. Interrogating published single-cell RNA-sequencing data we validated this mechanism in a different mouse model. Translational relevance of the results was provdied by in silco analyses of available human NEPC datasets, and by immunofluorescence on patient-derived adenocarcinoma and NEPC lesions. Overall, our results show that MCs actively inhibit NEPC, paving the way for innovative MC-based therapies for this fatal tumor. We also highlight SDC1 as a potential biomarker for incipient NEPC.

ZEB1 shapes AML immunological niches, suppressing CD8 T cell activity while fostering Th17 cell expansion.

Acute myeloid leukemia (AML) progression is influenced by immune suppression induced by leukemia cells. ZEB1, a critical transcription factor in epithelial-to-mesenchymal transition, demonstrates immune regulatory functions in AML. Silencing ZEB1 in leukemic cells reduces engraftment and extramedullary disease in immune-competent mice, activating CD8 T lymphocytes and limiting Th17 cell expansion. ZEB1 in AML cells directly promotes Th17 cell development that, in turn, creates a self-sustaining loop and a pro-invasive phenotype, favoring transforming growth factor ß (TGF-ß), interleukin-23 (IL-23), and SOCS2 gene transcription. In bone marrow biopsies from AML patients, immunohistochemistry shows a direct correlation between ZEB1 and Th17. Also, the analysis of ZEB1 expression in larger datasets identifies two distinct AML groups, ZEB1high and ZEB1low, each with specific immunological and molecular traits. ZEB1high patients exhibit increased IL-17, SOCS2, and TGF-ß pathways and a negative association with overall survival. This unveils ZEB1's dual role in AML, entwining pro-tumoral and immune regulatory capacities in AML blasts.