HLA reduction of human T cells facilitates generation of immunologically multicompatible cellular products

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

Journal

Blood Advances American Society of Hematology

Book Volume: 8

Pages Range: 3416-3426

Journal Issue: 13

DOI: 10.1182/bloodadvances.2023011496

Abstract

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.

Authors with CRIS profile

Philipp Hilgendorf Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene

Involved external institutions

Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE) Helmholtz-Zentrum für Infektionsforschung (HZI) DE Germany (DE)

How to cite

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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