Oral tolerance can prevent unnecessary immune responses against dietary antigens. Members of the B7 protein family play critical roles in the positive and/or negative regulation of T cell responses to interactions between APCs and T cells. V-set and Ig domain-containing 4 (VSIG4), a B7-related co-signaling molecule, has been known to act as a co-inhibitory ligand and may be critical in establishing immune tolerance. Therefore, we investigated the regulation of VSIG4 signaling in a food allergy and experimental oral tolerance murine models. We analyzed the contributions of the two main sites involved in oral tolerance, the mesenteric lymph node (MLN) and the liver, in VSIG4-mediated oral tolerance induction. Through the comparative analysis of major APCs, dendritic cells (DCs) and macrophages, we found that Kupffer cells play a critical role in inducing regulatory T cells (Tregs) and establishing immune tolerance against oral antigens via VSIG4 signaling. Taken together, these results suggest the possibility of VSIG4 signaling-based regulation of orally administered antigens.

The number of lung cancer patients is increasing every year worldwide. For these patients' treatment, not only anticancer drugs but also immune anticancer drugs are rapidly being developed. So far, the PD-1 antibody is widely used in treating NSCLC patients, and various pharmaceutical companies are continuously developing it. However, in PD-L1 low or negative patients, new drugs are required because there are no appropriate drugs. Of course, the PD-1 antibody is sometimes used, but the response rate is low, so new therapeutic drugs are needed.We identified a new target for PD-L1 low or negative patients using PD-L1 negative or positive lung cancer tissues. The new target's code name is "Target protein A." Target protein A expressed higher in tumor than normal. As a result of analyzing caucasian lung cancer patients' tissues by immunohistochemistry, 36% of cases expressed "Target protein A". Moreover, we also confirmed that target protein A was higher in tumors than normal through the TCGA database. Based on these results, we developed an immune anticancer drug (WM-A1) targeting Target protein A and demonstrated that it induces cancer cell death by inhibiting the binding with the binding partner protein B. Meanwhile, to clarify the relationship between PD-L1 and Target protein A, we analyzed the expression between the two proteins in lung cancer cell lines and proved that they exhibit reverse correlation. Among PD-L1 low or negative lung cancer patient tissues, about 32.75% of tissues expressed Target protein A. Conversely, among the patient samples expressing Target protein A, the PD-L1 low or negative population was 63%. We checked a similar trend through the TCGA database. For the efficacy of WM-A1, we confirmed that WM-A1 induced T cell-mediated cell death in a co-culture system with human PBMC and secreted major cytokines. In addition, we revealed that the group transplanted with a cell line expressing Target protein A in the PBMC humanized model showed high immuno-anticancer efficacy. Furthermore, we demonstrated that WM-A1 increased T cell activation and related cytokine expression. However, there was no reactivity to the PD-1 antibody because it expressed Target protein A and did not express PD-L1.Therefore, we suggest that WM-A1 is a new therapeutic antibody for the PD-L1 low or negative patient population. Based on these findings, we are planning a preclinical study (GLP-Tox) in 2021. #Corresponding author: Dong-Hoon Jin*These authors (Hye jin Son and Minki Lee) contributed equally to this work. Citation Format: Hye jin Son, Minki Lee, Seongrak Kim, Jai-Hee Moon, Hana Kim, Wonhwa Shin, Joseph Kim, Mi So Lee, Daeun Kim, Seunggeon Bae, Joonyee Jeong, Seung-Woo Hong, Chun-Ho Park, Hyun Ho Lee, Dong-Hoon Jin. New therapeutic antibody ("WM-A1") for treatment of low or no PD-L1 NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1216.