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. Here, we show that translationally controlled tumor protein (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. To explore therapeutic applicability, we generated anti-TCTP antibodies for TCTP inhibition. The antibodies successfully neutralized TCTP in molecular and cellular level. The antibodies also suppressed PMN-MDSC accumulation and tumor growth. The combination of anti-TCTP antibody and immune checkpoint inhibitor showed synergistic effect on tumor growth inhibition. In conclusion, extracellular TCTP is an immunomodulator recruiting PMN-MDSCs to TIME. When TCTP is removed or neutralized, PMN-MDSC counts in TIME decreased. Anti-TCTP therapy may offer a new immunotherapy strategy.

Citation Format: Jeong-Hyun Ryou, Gwanghee Lee, Tadatsugu Taniguchi, Hideyuki Yanai, Sho Hangai. TCTP is a target for cancer immunotherapy modulating myeloid-derived suppressor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 242.