Tumor-intrinsic ST3GAL3 Activity Blunts Anti-tumor Immune and Drives Immunotherapy Resistance in Ovarian Cancer
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ABSTRACT: ST3GAL3 is a α2,3-sialyltransferase and involves in α2,3 sialylation in tumors; however, its role in the tumorigenic capacity of malignant cells and anti-tumor immune remains largely unexplored. Here, HM1 cells were stably transfected using lentivirus expressing a shRNA targeting ST3GAL3 (HM1-shST3GAL3) or scramble shRNA as control (HM1-shControl). Then, HM1-shControl or HM1-shST3GAL3 cells were injected into the right flank of B6C3F1 mice using a 27 g needle. ST3GAL3 knockdown significantly compromised tumor growth at a immune-dependant manner. Mechanistically, ST3GAL3 knockdown enhances pro-inflammatory phenotype of macrophages, leading ultimately to activation and recruitmentof CD8+ T cells. Moreover, we identified ST3GAL3 as a potential novel biomarker for bevacizumab or immune checkpoint blockade (ICB) intervention. ST3GAL3 knockdown in tumors also be useful to improve cancer immunotherapies.
Project description:ST3GAL3 is a α2,3-sialyltransferase and involves in α2,3 sialylation in tumors; however, its role in the tumorigenic capacity of malignant cells and anti-tumor immune remains largely unexplored. Here, HM1 cells were stably transfected using lentivirus expressing a shRNA targeting ST3GAL3 (HM1-shST3GAL3) or scramble shRNA as control (HM1-shControl). Then, HM1-shControl or HM1-shST3GAL3 cells were injected into the right flank of B6C3F1 mice using a 27 g needle. ST3GAL3 knockdown significantly compromised tumor growth at a immune-dependant manner. Mechanistically, ST3GAL3 knockdown enhances pro-inflammatory phenotype of macrophages, leading ultimately to activation and recruitmentof CD8+ T cells. Moreover, we identified ST3GAL3 as a potential novel biomarker for bevacizumab or immune checkpoint blockade (ICB) intervention. ST3GAL3 knockdown in tumors also be useful to improve cancer immunotherapies.
Project description:Immunosuppressive tumor microenvironments (TME) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSC), precursors to cancer-associated fibroblasts (CAFs), dictate tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells that results in inhibition of effector functions. The role of sialylation in dictating MSC/CAF immunosuppression in the TME is unknown. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory PD-1, Siglec-7 and Siglec-9-expressing T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as evidenced by infiltration of CD25 and granzyme B-expressing T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.
Project description:HSPD1 knockdown was established in A549 cells using an shRNA approach. Secretomes from both shHSPD1-A549 and shControl-A549 cells were collected and subjected to label-free comparative proteome analysis using SWATH-MS.
Project description:Dynamic change of glycosylation is found in various cancers; however, the precise role of glycosylation in metastasis is remained largely unknown. Current study show that α2,6-sialylation or β-galactoside α2,6-sialyltransferase (ST6Gal1) inhibits circulating tumor cell aggregation and depletion or restoration of α2,6-sialylation in patient derived xenograft model amplified or diminished cell aggregation and lung metastasis.
Project description:To examine the role of ALDH1A1 in bladder cancer patient-derived cells (PDCs), BC-1 and -2 cells were treated with shRNA targeting ALDH1A1 (shALDH1A1) or control shRNA (shControl). ALDH1A1 knockdown study showed that TUBB3 is one of the downregulated genes in PDCs.
Project description:To identify changes in splicing patterns following TARBP2 knockdown, RNA-sequencing was performed on nuclear RNA extracted from cells expressing shRNAs targeting TARBP2 or a non-targeting shRNA (shControl).
Project description:To explore the role of Dusp18 in regulating the immune microenvironment of colorectal cancer (CRC), we established MC38 knockdown via shRNA and performed the proteomics.
Project description:We report the gene expression profiling of mouse BC CML model which were knockdown with either shControl or shAMD1 constructs. By obtaining RNA from primary BC CML cells from those mice (n: 3 for each shRNA),we find that thousands gene were dysregulated by AMD1 knockdown.
Project description:We generated two mouse podocyte cell lines stably transduced with either a shControl lentiviral construct or a shRNA lentiviral construct designed to target Tug1 RNA to investigate the consequences on the gene expression profile of Tug1 knockdown in differentiated mouse podocytes
Project description:HNRNPC plays an important role in HCC metastasis, HNRNPC knockdown by specific shRNA (HNRNPC-shRNA) significantly inhibited the migration and invasion of MHCC97H cells, while HNRNPC overexpression exerted the opposite effect. To elucidate the mechanisms by which HNRNPC facilitated HCC metastasis, we performed microarray analysis to compare the transcription profiling between the MHCC97H-shcontrol and MHCC97H-shHNRNPC cells.