Establishment of a detection platform for glioblastoma-dendritic cell (DC) vaccine preparation and to determine the efficacy of the vaccine in a clinical trial. Autologous glioblastoma-DC vaccine was prepared from a glioblast specimen procured from surgical resection. The specimen was used to enrich the vaccine with peripherally blood-derived DCs after heat-shock induced, glioblastoma apoptosis. The control group received conventional treatment of surgery and radio-chemotherapy post-operation. The therapeutic group received a combination of glioblastoma-DC vaccine and conventional therapy. A comparison of the functional immune parameters, including tumor control, rate live time, Karnofsky scores, and complications occurring in each group were observed and recorded. The proportions of peripheral CD3(+), CD3(+)CD4(+), CD4(+)/CD8(+), and NK cells were significantly higher after DC vaccination than the control group (P < 0.05). Serum levels of IL-2, IL-12, and IFN-γ were significantly higher after DC vaccination than in the control group (P < 0.05). Nine months after vaccination, tumor control rate is significantly improved in the DC group compared with the control group (P < 0.05); survival rate was significantly higher in DC group than in control group (P < 0.05) and the time to relapse was significantly longer in DC group than that in control group (P < 0.05). Karnofsky scores were better in DC vaccination group 6 and 9 months post-treatment compared with the control group (P < 0.05). The combination of glioma DC vaccine and radiotherapy/chemotherapy post-operatively enhances the immune function of patients, increases the tumor control rate, prolongs the survival time and relapse duration, improves the quality of life, and therefore provides a more effective intervention of treating glioblastoma.

Radioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGF-β2 expression by directly reducing H3K9me3 level at the TGF-β2 promoter and then activates Smad/ATM/Chk2 signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner that deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β2/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β2/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.

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BackgroundAlthough immune checkpoint blockade (ICB) has been proven to achieve a persistent therapeutic response in various tumor types, only 20%–40% of patients benefit from this treatment. Radiotherapy (RT) can enhance tumor immunogenicity and improve the ICB response, but the outcome achieved by combining these two modalities remains clinically unsatisfactory. We previously uncovered that lysine-specific demethylase 4C (KDM4C) is a regulator of radiosensitivity in lung cancer. However, the role of KDM4C in antitumor immunity has not yet been investigated.MethodsInfiltrating immune cells in our mouse tumor model were screened by flow cytometry. An in vivo subcutaneous transplanted tumor model and in vitro conditioned culture model were constructed to detect the quantitative and functional changes in CD8+ T cells. RNA sequencing and chromatin immunoprecipitation-PCR assays were used to explore the downstream regulatory mechanism of KDM4C in antitumor immunity. A C57BL/6 mouse tumor model was developed to evaluate the efficacy and safety of a triple therapy (the KDM4C-specific inhibitor SD70 plus RT and an anti-PD-L1 antibody) in lung cancer in vivo.ResultsGenetical or pharmacological inhibition of KDM4C specifically increased CD8+ T cell infiltration; promoted the proliferation, migration and activation of CD8+ T cells; and alleviated CD8+ T cell exhaustion in mouse tumor tissues. Mechanistically, KDM4C inhibition increased the binding of H3K36me3 to the CXCL10 promoter region, thus inducing CXCL10 transcription and enhancing the CD8+ T cell mediated antitumor immune response. More importantly, among the tested regimens, the triple therapy achieved the best therapeutic efficacy with tolerable toxicity in lung cancer.ConclusionsOur data reveal a crucial role for KDM4C in antitumor immunity in lung cancer and indicate that targeting KDM4C in combination with radioimmunotherapy might be a promising synergistic strategy in lung cancer.