Prostate cancer (PCa) is a type of potentially fatal malignant tumor. Immunotherapy has shown a lot of potential for various types of solid tumors, but the benefits have been less impressive in PCa. Enhancer of zeste homolog 2 (EZH2) is one of the three core subunits of the polycomb repressive complex 2 that has histone methyltransferase activity, and the immune effects of EZH2 in PCa are still unclear. The purpose of this study was to explore the potential of EZH2 as a prognostic factor and an immune therapeutic biomarker for PCa, as well as the expression pattern and biological functions. All analyses in this study were based on publicly available databases, mainly containing Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), UCSCXenaShiny, and TISIDB. We performed differential expression analysis, developed a prognostic model, and explored potential associations between EZH2 and DNA methylation modifications, tumor microenvironment (TME), immune-related genes, tumor mutation burden (TMB), tumor neoantigen burden (TNB), and representative mismatch repair (MMR) genes. We also investigated the molecular and immunological characterizations of EZH2. Finally, we predicted immunotherapeutic responses based on EZH2 expression levels. We found that EZH2 was highly expressed in PCa, was associated with a poor prognosis, and may serve as an independent prognostic factor. EZH2 expression in PCa was associated with DNA methylation modifications, TME, immune-related genes, TMB, TNB, and MMR. By gene set enrichment analysis and gene set variation analysis, we found that multiple functions and pathways related to tumorigenesis, progression, and immune activation were enriched. Finally, we inferred that immunotherapy may be more effective for PCa patients with low EZH2 expression. In conclusion, our study showed that EZH2 could be a potentially efficient predictor of prognosis and immune response in PCa patients.
Background Charged particle beams from protons to carbon ions provide many significant physical benefits in radiation therapy. However, preclinical studies of charged particle therapy for prostate cancer are extremely limited. The aim of this study was to comprehensively investigate the biological effects of charged particles on prostate cancer from the perspective of in vitro studies. Methods We conducted a systematic review by searching EMBASE (OVID), Medline (OVID), and Web of Science databases to identify the publications assessing the radiobiological effects of charged particle irradiation on prostate cancer cells. The data of relative biological effectiveness (RBE), surviving fraction (SF), standard enhancement ratio (SER) and oxygen enhancement ratio (OER) were extracted. Results We found 12 studies met the eligible criteria. The relative biological effectiveness values of proton and carbon ion irradiation ranged from 0.94 to 1.52, and 1.67 to 3.7, respectively. Surviving fraction of 2 Gy were 0.17 ± 0.12, 0.55 ± 0.20 and 0.53 ± 0.16 in carbon ion, proton, and photon irradiation, respectively. PNKP inhibitor and gold nanoparticles were favorable sensitizing agents, while it was presented poorer performance in GANT61. The oxygen enhancement ratio values of photon and carbon ion irradiation were 2.32 ± 0.04, and 1.77 ± 0.13, respectively. Charged particle irradiation induced more G0-/G1- or G2-/M-phase arrest, more expression of γ-H2AX, more apoptosis, and lower motility and/or migration ability than photon irradiation. Conclusions Both carbon ion and proton irradiation have advantages over photon irradiation in radiobiological effects on prostate cancer cell lines. Carbon ion irradiation seems to have further advantages over proton irradiation. Graphical Abstract
Background and purpose Carbon ion is radiobiologically more effective than photons and are beneficial for treating radioresistant tumors, several animal experiment with tumor-bearing suggest that carbon ion beam irradiation in combination with immunotherapy yields better results, especially in controlling distant metastases, which suggests that carbon ion beam induces a different anti-tumor immune response than photon beam, more complex molecular mechanisms need to be further explored. We conduct this in vivo and in vitro experiment was to investigate the radio-immune effects and its mechanism of different LET rays combined PD-1 inhibitors.Methods and Materials: Lewis lung adenocarcinoma cells and C57BL/6 mice were stablished tumor-bearing mouse model, the irradiated tumor located on the left back and the non-irradiated tumor located on the right hind limb. The left back tumor was irradiated with 10Gy X-ray or carbon ion beam, combined with or without PD-1 inhibitor. Immunohistochemistry was used to detect the expression of immunogenicity-related molecules and the infiltration of CD8 + T cells in tumor tissues. ELISA was used to detect the changes of IFN-β in mouse serum, and flow cytometry was used to detect the changes of CD8 + T cells in mouse peripheral blood. Lewis cells were irradiated with different doses of X-ray and carbon ion. The changes of TREX1, PD-L1, and IFN-β in mRNA and protein levels were detected with RT-PCR or Western blot respectively. TREX1 knockdown were constructed by siRNA transfection and irradiated with different rays. Changes in cell proliferation, viability, apoptosis rate were detected using CCK8 assay, BrdU assay, and flow cytometry.Results X-ray or carbon ion combined with αPD-1 had a significant inhibitory effect on bilateral tumors, especially carbon ion in non-irradiated side tumor(p < 0.05). 10 Gy carbon ion irradiation enhanced the proportion of infiltrating CD8 + T cells and the expression level of IFN-β in irradiated side tumor, however, it also increased PD-L1 and TREX1 expression level. Lewis cell in vitro experiment further confirmed that both X-ray and carbon ion irradiation can up-regulate the expression levels of PD-L1 and TREX1 with dose-dependent in tumor, especially the trend of up-regulation TREX1 is more obvious at a higher dose in carbon ions, i.e 8 or 10Gy, while the level of IFN-βis decreased. By gene silencing TREX1, IFN-βlevels were also significantly increased under hypofractioned dose with carbon ion irradiation.Conclusions The combination of X-ray or carbon ion irradiation and PD-1 inhibitors produce better anti-tumor effect and trigger abscopal effect on Lewis lung adenocarcinoma bearing mice through enhanced tumor immunogenicity and increased CD8 + T infiltration in TME via a threshold dose. TREX1 could serve as a prognostic marker and potential target of immunotherapy.
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