PDF(Pubmed)
Abstract：
Inadequate antigen-specific T cells activation hampers immunotherapy due to complex antigen presentation. In addition, therapeutic in vivo T cell expansion is constrained by slow expansion rates and limited functionality. Herein, we introduce a model fusion protein termed antigen-presenting cell-mimic fusion protein (APC-mimic), designed to greatly mimicking the natural antigen presentation pattern of antigen-presenting cells and directly expand T cells both in vitro and in vivo. The APC-mimic comprises the cognate peptide-human leukocyte antigen (pHLA) complex and the co-stimulatory marker CD80, which are natural ligands on APCs. Following a single stimulation, APC-mimic leads to an approximately 400-fold increase in the polyclonal expansion of antigen-specific T cells compared with the untreated group in vitro without the requirement for specialized antigen-presenting cells. Through the combination of single-cell TCR sequencing (scTCR-seq) and single-cell RNA sequencing (scRNA-seq), we identify an approximately 600-fold monoclonal expansion clonotype among these polyclonal clonotypes. It also exhibits suitability for in vivo applications confirmed in the OT-1 mouse model. Furthermore, T cells expanded by APC-mimic effectively inhibits tumor growth in adoptive cell transfer (ACT) murine models. These findings pave the way for the versatile APC-mimic platform for personalized therapeutics, enabling direct expansion of polyfunctional antigen-specific T cell subsets in vitro and in vivo.
摘要：
由于复杂的抗原呈递，抗原特异性T细胞活化不足会阻碍免疫治疗。此外,治疗性体内T细胞扩增受限于缓慢的扩增速率和有限的功能性。在这里，我们引入了一种称为抗原呈递细胞模拟融合蛋白（APC模拟物）的模型融合蛋白，旨在极大地模拟抗原呈递细胞的天然抗原呈递模式，并在体外和体内直接扩增T细胞。APC模拟物包含同源肽-人白细胞抗原(pHLA)复合物和共刺激标记CD80,它们是APC上的天然配体。在一次刺激之后，在不需要专门的抗原呈递细胞的情况下,与未处理组相比,APC模拟物导致抗原特异性T细胞的多克隆扩增增加约400倍。通过单细胞TCR测序（scTCR-seq）和单细胞RNA测序（scRNA-seq）的结合，我们在这些多克隆克隆型中鉴定出大约600倍的单克隆扩增克隆型.它还表现出在OT-1小鼠模型中证实的体内应用的适用性。此外，通过APC模拟物扩增的T细胞有效抑制过继性细胞转移(ACT)鼠模型中的肿瘤生长。这些发现为个性化治疗的多功能APC模拟平台铺平了道路，能够在体外和体内直接扩增多功能抗原特异性T细胞亚群。
