Background Programmed cell death protein 1 (PD-1) antibody has been approved for a variety of tumors, but its effective rate is unsatisfactory. New evidence suggests that mast cells are an important component of the tumor microenvironment and are associated with resistance to immunotherapy, but the underlying mechanism is not clear. Methods Bioinformatics analysis of patients with melanoma in TCGA-SKCM and GSE91061 was used to determine the prognostic value of mast cells and their association with anti-PD-1 immunotherapy. HMC-1 cells (mast cell line) and bone marrow-derived mast cells (BMMCs) were used to verify the effect of PD-1 antibody and cromolyn sodium in vitro. The mouse subcutaneous melanoma model was used to verify the effect of the PD-1 antibody on mast cells in vivo. Results Bioinformatics analysis showed that mast cells were a poor prognostic factor associated with resistance to anti-PD-1 immunotherapy. PD-1 was expressed on the mast cell membrane. The PD-1 antibody promoted the release of histamine and cytokines from mast cells via the PI3K/AKT pathway and calcium signaling pathway. The activation of mast cells induced by PD-1 antibody could be partially inhibited by cromolyn sodium. In vivo, cromolyn sodium increased the efficacy of PD-1 antibody and decreased the infiltration of mast cells and the density of microvessels. Conclusion PD-1+ mast cell activated by PD-1 antibody plays a negative role in the tumor microenvironment via the enhanced function of releasing histamine and cytokines. Inhibition of mast cell may provide a new solution to solve the low response rate of anti-PD-1 immunotherapy.
Lysine crotonylation is a recently discovered post-translation modification involved in transcription regulation, cell signal transduction, and other processes. Scientists have identified several crotonylases and decrotonylases of histones, including P300/CBP, HDACs, and SIRTs. However, the regulation of non-histone protein crotonylation remains unclear. In the current study, we verified that crotonylation was upregulated in hypoxia and promoted liver cancer cell growth. We performed TMT-labeled quantitative lysine crotonylome analysis in 12 pairs of hepatocellular carcinoma and adjacent liver tissue and identified 3,793 lysine crotonylation sites in 1,428 proteins. We showed that crotonylation of lamin A at the site of K265/270 maintains its subcellular position, promotes liver cancer cell proliferation, and prevents cellular senescence. Our data indicate that HDAC6 is the decrotonylase of lamin A and downregulated in response to hypoxia, resulting in lamin A K265/270cr. Taken together, our study reveals the lamin A crotonylation in liver cancer progression and fills the research gap in non-histone protein crotonylation function.
Background Chemoradiotherapy‐induced PD‐L1 upregulation leads to therapeutic resistance and treatment failure. The PD‐1/PD‐L1 blocking antibodies sensitize cancers to chemoradiotherapy by blocking extracellular PD‐1 and PD‐L1 binding without affecting the oncogenic function of intracellular PD‐L1. Reversing the chemoradiation‐induced PD‐L1 expression could provide a new strategy to achieve a greater anti‐tumour effect of chemoradiotherapy. Here, we aimed to identify candidate small molecular inhibitors that might boost the anti‐tumour immunity of chemoradiotherapy by decreasing treatment‐induced PD‐L1 expression in non‐small cell lung cancer (NSCLC). Methods A drug array was used to recognize compounds that can suppress the cisplatin‐induced and radiation‐induced PD‐L1 expression in NSCLC via the flow cytometry‐based assay. We examined whether and how targeting bromodomain containing 4 (BRD4) inhibits chemoradiation‐induced PD‐L1 expression and evaluated the effect of BRD4 inhibition and chemoradiation combination in vivo. Results BRD4 inhibitors JQ1 and ARV‐771 were identified as the most promising drugs both in the cisplatin and radiation screening projects in two NSCLC cell lines. Targeting BRD4 was supposed to block chemoradiotherapy inducible PD‐L1 expression by disrupting the recruitment of BRD4‐IRF1 complex to PD‐L1 promoter. A positive correlation between BRD4 and PD‐L1 expression was observed in human NSCLC tissues. Moreover, BRD4 inhibition synergized with chemoradiotherapy and PD‐1 blockade to show a robust anti‐tumour immunity dependent on CD8+ T cell through limiting chemoradiation‐induced tumour cell surface PD‐L1 upregulation in vivo. Notably, the BRD4‐targeted combinatory treatments did not show increased toxicities. Conclusion The data showed that BRD4‐targeted therapy synergized with chemoradiotherapy and anti‐PD‐1 antibody by boosting anti‐tumour immunity in NSCLC.
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