OP06 TCTP is a target for cancer immunotherapy-modulating myeloid-derived suppressor cells

[摘要] Background: Myeloid-derived suppressor cells (MDSCs) are a heterogenous group ofmyeloid cells that are highly suppressive to antitumor lymphocyte function andtrafficking 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 obstaclesimposed by TIME contribute to a great extent.Methods: Translationally controlled tumor protein (TCTP) was identified in supernatants from necrotic cells. After the identification, recombinant TCTP was used forbiochemical 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 wasdownloaded via the cBioPortal. Anti-TCTP antibody was generated by mouse immunization and phage display methods.Results: We show that TCTP released by dying tumor cells is an immunomodulatorcrucial to full-blown MDSC accumulation in the TIME in mouse models. We provideevidence that extracellular TCTP mediates recruitment of the polymorphonuclearMDSC (PMN-MDSC) population in the TIME, which is Toll- like receptor-2 (TLR2)dependent. For human translation, we confirmed that human TCTP binds directly tohuman TLR2 extracellular domain and stimulates human PBMC to produce multiplecytokines. We measured TCTP levels in the serum of human patients with colorectalcancer (CRC). Consistent with our mouse models, TCTP levels were higher in serumsamples of patients with cancer. Of note, patients with amplified TCTP alleles hadsignificantly lower progression-free survival. Anti-TCTP antibodies successfullyneutralized TCTP in molecular and cellular level. The antibodies also suppressed PMNMDSC accumulation and tumor growth, showing therapeutic applicability. The combination of anti-TCTP antibody and immune checkpoint inhibitor showed synergisticeffect on tumor growth inhibition.Conclusions: Extracellular TCTP is an immunomodulator recruiting PMN-MDSCs toTIME. 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 inversecorrelation between TCTP expression and an anti-tumor immune signature, suggesting that TCTP-mediated immunosuppression operates in human cancers. AntiTCTP therapy may offer a new immunotherapy strategy.

[学科分类] 社会科学、人文和艺术（综合）

[关键词] MDSC;TCTP;Immunotherapy