TCR 과 Co-stimulatory ICD 직접 연결 엔지니어링을 통한 TCR-T 기능 향상 가능성

Abstract

This study proposes a novel approach to enhance the efficacy of adoptive T cell therapy (ACT), a form of immunotherapy for cancer treatment. Among ACT strategies, T cell receptor-engineered T (TCR-T) therapy can be applied to solid tumors by expressing TCRs on patient T cells to recognize tumor antigens and eradicate cancer cells. However, a significant challenge in ACT is the limited activation of T cells within the tumor microenvironment, leading to suppressed immune responses and reduced effectiveness. Therefore, we investigated methods to improve T cell function using the TCR-T system. Similar to techniques used in Chimeric Antigen Receptor T (CAR-T) therapies, we designed an engineering approach to directly link the intracellular domain (ICD) of co-stimulatory molecules to the TCR constant region. We aimed to assess the impact of this modification on T cell activation and anti-tumor effects. Using lentivirus-mediated gene delivery, we confirmed stable TCR expression levels in both cell lines and human primary cells. However, contrary to expectations, this modification did not enhance anti-tumor effects compared to conventional TCR in human primary cells; in some cases, these effects were diminished. Nevertheless, the engineering approach of directly linking the ICD of co-stimulatory molecules statistically significantly increased T cell activation levels compared to conventional TCR. These results resemble enhanced activation responses observed in CAR-T research, demonstrating the feasibility of a second-generation TCR-T system that successfully integrates signals 1 and 2. Therefore, the direct coupling of co-stimulatory molecule ICD to TCR via engineering provides a new strategy in TCR-T engineering to enhance ACT functionality, suggesting potential improvements in the field of immune oncology therapy