LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer.

BACKGROUND: Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown. METHODS: Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA). RESULTS: Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo. CONCLUSION: LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.

SDC: An integrated database for sex differences in cancer.

Sex differences are evident in the incidence and mortality of diverse cancers. With the development of personalized approaches in cancer treatment, the impact of sex differences has not been systematically incorporated into preclinical and clinical cancer research. The molecular mechanisms underlying sex differences in cancer have not been elucidated. Here, we developed the first database of Sex Differences in Cancer (SDC), a web-based public database that integrates resources from multiple databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), UCSC Xena, Broad Institute Cancer Cell Line Encyclopedia (CCLE), Genomics of Drug Sensitivity in Cancer (GDSC). SDC contains 27 types of cancers, 6 types of molecular data, more than 10,000 donors, 977 cancer cell lines were used to analyze sex differences among cancers. It provides five main modules: Survival and phenotype, Molecular differences, Signatures and pathways, Therapy response, Download. Users can download the all the visualized results and raw data after analysis. Collectively, SDC is the first integrated database to analyze sex differences in cancer on the web server, which will strengthen our understanding of the role of sex in cancers. It is implemented in Shiny-server and freely available for public use at http://sdc.anticancer.xyz.