AUTHOR=Garcia-Rodriguez Patricia , Hidalgo Laura , Rodriguez-Milla Miguel Angel , Somovilla-Crespo Beatriz , Garcia-Castro Javier 

TITLE=LIN28 upregulation in primary human T cells impaired CAR T antitumoral activity

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1462796

DOI=10.3389/fimmu.2024.1462796

ISSN=1664-3224

ABSTRACT=<p>LIN28, a highly conserved RNA-binding protein that acts as a posttranscriptional modulator, plays a vital role in the regulation of T-cell development, reprogramming, and immune activity in infectious diseases and T-cell-based immunotherapies. LIN28 inhibit the expression of <italic>let-7</italic> miRNAs, the most prevalent family of miRNAs in lymphocytes. Recently it has been suggested that <italic>let-7</italic> enhances murine anti-tumor immune responses. Here, we investigated the impact of LIN28 upregulation on human T cell functions, focusing on its influence on CAR T cell therapy. LIN28 lentiviral transduction of human T cells led to a stable expression of LIN28 that significantly downregulated the <italic>let-7</italic> miRNA family without affecting cell viability or expansion potential. LIN28 overexpression maintained human T cell phenotype markers and functionality but impaired the antitumoral cytotoxicity of NKG2D-CAR T cells both <italic>in vitro</italic> and <italic>in vivo</italic>. These findings highlight the intricate relationship between LIN28/<italic>let-7</italic> axis and human T cell functionality, including in CAR T cell therapy.</p>