Winterhalter PM, Warmuth L, Hilgendorf P, Schütz JM, Dötsch S, Tonn T, Cicin-Sain L, Busch DH, Schober K (2024)
Publication Type: Journal article
Publication year: 2024
Book Volume: 8
Pages Range: 3416-3426
Journal Issue: 13
DOI: 10.1182/bloodadvances.2023011496
Adoptive cellular therapies have shown enormous potential but are complicated by personalization. Because of HLA mismatch, rejection of transferred T cells frequently occurs, compromising the T-cell graft’s functionality. This obstacle has led to the development of HLA knock-out (KO) T cells as universal donor cells. Whether such editing directly affects T-cell functionality remains poorly understood. In addition, HLA KO T cells are susceptible to missing self-recognition through natural killer (NK) cells and lack of canonical HLA class I expression may represent a safety hazard. Engineering of noncanonical HLA molecules could counteract NK-cell recognition, but further complicates the generation of cell products. Here, we show that HLA KO does not alter T-cell functionality in vitro and in vivo. Although HLA KO abrogates allogeneic T-cell responses, it elicits NK-cell recognition. To circumvent this problem, we demonstrate that selective editing of individual HLA class I molecules in primary human T cells is possible. Such HLA reduction not only inhibits T-cell alloreactivity and NK-cell recognition simultaneously, but also preserves the T-cell graft’s canonical HLA class I expression. In the presence of allogeneic T cells and NK cells, T cells with remaining expression of a single, matched HLA class I allele show improved functionality in vivo in comparison with conventional allogeneic T cells. Since reduction to only a few, most frequent HLA haplotypes would already be compatible with large shares of patient populations, this approach significantly extends the toolbox to generate broadly applicable cellular products.
APA:
Winterhalter, P.M., Warmuth, L., Hilgendorf, P., Schütz, J.M., Dötsch, S., Tonn, T.,... Schober, K. (2024). HLA reduction of human T cells facilitates generation of immunologically multicompatible cellular products. Blood Advances, 8(13), 3416-3426. https://doi.org/10.1182/bloodadvances.2023011496
MLA:
Winterhalter, Pascal M., et al. "HLA reduction of human T cells facilitates generation of immunologically multicompatible cellular products." Blood Advances 8.13 (2024): 3416-3426.
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