Abstract 592: TLT2 expressed on B cells and Bregs suppresses T cell activity, and treatment of the anti-TLT2 antibody, GENA-105S05, induces tumor growth inhibition in a syngeneic mouse model

Abstract

Abstract TLT2 (TREML2, Triggering Receptor Expressed on Myeloid cells Like transcript 2) is a single-pass type I membrane protein that contains an immunoglobulin-like domain. Previous studies have shown that TLT2 is up-regulated in response to inflammation in macrophages, suggesting a potential role in the pro-inflammatory response. However, the function of TLT2 in immune cells and crosstalk of cells expressing TLT2 with other immune cells, e.g., T cells, have not been studied. Therefore, we tried to search immune cells expressing TLT2 and explore the effect of TLT2 on T cell activity. T cell proliferation and cytokine secretion assays using TLT2 recombinant protein showed that TLT2 significantly inhibits T cells proliferation and cytokine secretion (IFN gamma and TNF alpha) more than PD-L1. Since TLT2 can act as an immune checkpoint protein, FACS analysis was performed on various cancer cell lines and immune cells to confirm the expression of TLT2. TLT2 was commonly expressed on human and mouse B cells but not cancer cells. Additionally, we found that TLT2 was expressed on human and mouse regulatory B cells (Bregs). Bregs represent a subpopulation of B cells that inhibit effector T cells but induce regulatory T cells and attenuate the anti-tumor effect of tumor-infiltrating immune cells in the tumor microenvironment. Bregs are also closely related to various clinicopathological factors and the survival rates of cancer patients. In particular, Bregs are observed to be high in the patient group not responding to the administration of immunotherapy. Therefore, Bregs could be a potential therapeutic target for immunotherapy of cancer patients. For in vivo function study of TLT2, we inoculated cancer cells in TLT2 WT (wild-type) and KO (knockout) mice and monitored the tumor growth. The size of tumors inoculated in TLT2 KO mice was reduced compared to TLT2 WT mice. In addition, the total population of CD4+ T cells and the population of CD4+ and CD8+ T cells that produce cytokines (IFN gamma and TNF alpha) were increased in the spleen and tumor-infiltrated lymphocyte of the TLT2 KO mice. Finally, we investigated the potential of TLT2 as a cancer immunotherapeutic target using a GENA-105S05, a monoclonal antibody against mouse Tlt2. GENA-105S05 significantly inhibited tumor growth in the MC38 syngeneic mouse tumor model. Further investigation on the function of TLT2 expressed in the Bregs and the development of a monoclonal antibody targeting TLT2 could lead to novel therapeutic interventions. Citation Format: Mi Young Cha, Bu-Nam Jeon, Hyunsuk Yang, Seungmin Byun, Areum Jeong, Joo-Yeon Chung, Sanggyun Kim, Kyung Mi Park, Hansoo Park. TLT2 expressed on B cells and Bregs suppresses T cell activity, and treatment of the anti-TLT2 antibody, GENA-105S05, induces tumor growth inhibition in a syngeneic mouse model [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 592.