849 Neutralizing extracellular TCTP overcomes MDSC-mediated immunosuppression and enhances cancer immunity

<h3>Background</h3> Modulating the tumor microenvironment (TME) with immune checkpoint inhibitors shows promise in cancer therapy by enhancing CD8+ T cell activity. However, many patients do not benefit possibly due to profound immunosuppression mediated by myeloid-derived suppressor cells (MDSC). These immature myeloid cells strongly inhibit anti-tumor activities of T and NK cells and stimulate regulatory T cells. Therefore, targeting MDSCs represents a new frontier in immunotherapy to improve treatment outcomes. We found that translationally controlled tumor protein (TCTP) released from dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TME.¹ <h3>Methods</h3> Extracellular role of TCTP in tumor growth was validated in syngeneic models with engineered cancer cell lines. Its impact on the TME was shown by increased cytokine mRNA expression and proliferating T cells in TCTP-treated PBMCs. TCTP-TLR2 interaction was confirmed via a reporter cell system. An antibody against TCTP, BIO101, neutralized this interaction in vitro and in vivo, with its tumor inhibition efficacy in vivo correlating with reduced MDSC levels in tumor-infiltrating lymphocytes. <h3>Results</h3> The tumor-promoting roles of TCTP were confirmed through multiple syngeneic mouse models using knockout and knock-in cancer cells. The interaction of TCTP with TLR2 was specifically observed in the TLR2-TLR6 heterodimer, but not in the TLR2-TLR1 heterodimer. When co-treated with monocytic MDSCs (M-MDSCs) and T cells isolated from human PBMCs, TCTP suppressed the proliferative potential of CD4 and CD8 T cells via M-MDSC activation. Besides activating M-MDSCs, TCTP also acts as a direct chemotactic agent. Upon injection into mice, TCTP mobilized a significant number of neutrophils within less than 2 hours, specifically affecting neutrophils but not lymphocytes. BIO101 is a fully human antibody derived from hybridoma technology that binds to both human and mouse TCTP. Its blocking capability was assessed by ELISA and cell-based assays showing interference with TCTP and TLR2 binding. In syngeneic mouse models, BIO101 exhibited a significant tumor growth inhibition dose-dependently and reduced MDSC frequency while increasing CD8 T cell frequency. BIO101 is currently in the lead optimization stage and will enter the preclinical stage soon. <h3>Conclusions</h3> Neutralizing extracellular TCTP with BIO101 effectively modulates MDSCs in the tumor microenvironment. This suggests significant clinical benefits for patients with immune-suppressive tumors characterized by high TCTP release. BIO101 shows promise as a novel therapeutic antibody, offering potential clinical benefits for patients with TCTP-high tumors. <h3>Reference</h3> Hangai S, Kawamura T, Kimura Y, <i>et al</i>. Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells. <i>Nat Immunol</i> 2021;<b>22</b>:947–957.