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• W4313367992 abstract "Myeloid-derived suppressor cells (MDSCs) are a heterogenous group of myeloid cells that are highly suppressive to antitumor lymphocyte function and trafficking to the tumor. The accumulation of MDSCs in the tumor immune microenvironment (TIME) makes immunosuppressive TIME and progressive tumor. In fact, despite notable clinical outcomes in cancer immunotherapy, many patients are refractory or relapsed to immune checkpoint inhibitor therapy, wherein obstacles imposed by TIME contribute to a great extent. Translationally controlled tumor protein (TCTP) was identified in supernatants from necrotic cells. After the identification, recombinant TCTP was used for biochemical and cell-based assays. For in vivo experiments, immunocompetent syngeneic mouse model was used. TCTP knock-out cell line was generated by CRISPR/Cas9-mediated genome engineering. The TCGA dataset of 640 patients with CRC was downloaded via the cBioPortal. Anti-TCTP antibody was generated by mouse immunization and phage display methods. We show that TCTP released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME in mouse models. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME, which is Toll- like receptor-2 (TLR2) dependent. For human translation, we confirmed that human TCTP binds directly to human TLR2 extracellular domain and stimulates human PBMC to produce multiple cytokines. We measured TCTP levels in the serum of human patients with colorectal cancer (CRC). Consistent with our mouse models, TCTP levels were higher in serum samples of patients with cancer. Of note, patients with amplified TCTP alleles had significantly lower progression-free survival. Anti-TCTP antibodies successfully neutralized TCTP in molecular and cellular level. The antibodies also suppressed PMN-MDSC accumulation and tumor growth, showing therapeutic applicability. The combination of anti-TCTP antibody and immune checkpoint inhibitor showed synergistic effect on tumor growth inhibition. Extracellular TCTP is an immunomodulator recruiting PMN-MDSCs to TIME. When TCTP is removed or neutralized, PMN-MDSC counts in TIME decreased. We also observed that TCTP expression is elevated in human cancer with an inverse correlation between TCTP expression and an anti-tumor immune signature, suggesting that TCTP-mediated immunosuppression operates in human cancers. Anti-TCTP therapy may offer a new immunotherapy strategy." @default.
• W4313367992 created "2023-01-06" @default.
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• W4313367992 date "2022-12-01" @default.
• W4313367992 modified "2023-09-30" @default.
• W4313367992 title "OP06 TCTP is a target for cancer immunotherapy-modulating myeloid-derived suppressor cells" @default.
• W4313367992 doi "https://doi.org/10.1016/j.esmoop.2022.100690" @default.
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