Abstract
Modification of specificity of T cells for the use in adoptive transfer (CAR- or TCR-redirected T cells) has revolutionized the therapy of liquid tumors and some infectious diseases. However, several obstacles are still hampering the efficacy of such potent therapy, hence concurrent modification of the function is also required to obtain successful results. Here we show the use of splice-switching antisense oligonucleotides (SSOs) as a tool to transiently modify T cell function. We demonstrate the possibility to transfect SSOs and an exogenous TCR into primary human T cells in the same electroporation reaction, without affecting viability and function of the transfected T lymphocytes. Moreover, we show that SSOs targeting T cell-specific mRNAs induce the skipping of the targeted exons, and the reduction of the protein and consequent modification of T cell function. This technical work paves the way to the use of SSOs in immune cells, not only for the knockdown of the functional isoform of the targeted proteins, but also for the protein manipulation by elimination of specific domains encoded by targeted exons.
Highlights
Adoptive T cell transfer is a versatile cell therapy modality that has the potential to address critical medical needs from chronic infections to oncology
Viral-infected host cells presenting viral antigens have been targeted by chimeric antigen receptors (CARs)/T cell receptors (TCRs)-redirected T cells against human immunodeficiency virus, hepatitis B virus (HBV), hepatitis C virus, human cytomegalovirus, or opportunistic fungal infections [1,2,3,4,5,6,7,8]
TCR mRNA and switching antisense oligonucleotides (SSOs) can be concurrently electroporated into T cells with no adverse effect
Summary
Through the engineering of effector T cells with specific receptors, in the form of chimeric antigen receptors (CARs) or classical T cell receptors (TCRs), one can direct the lytic action of CD8+ T cells against a specific target. Viral-infected host cells presenting viral antigens have been targeted by CAR/TCR-redirected T cells against human immunodeficiency virus, hepatitis B virus (HBV), hepatitis C virus, human cytomegalovirus, or opportunistic fungal infections [1,2,3,4,5,6,7,8]. To unleash the full clinical potential of adoptive T cell therapy beyond liquid tumors, two levels of cell engineering can be exploited—extrinsic and intrinsic.
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