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Expanded CD16+CD56+Granzyme B+ NK like CD8+ T cells an off target effect of bruton’s tyrosine kinase inhibitors in Waldenström macroglobulinemia
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Expanded CD16+CD56+Granzyme B+ NK like CD8+ T cells an off target effect of bruton’s tyrosine kinase inhibitors in Waldenström macroglobulinemia
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Journal Article
Expanded CD16+CD56+Granzyme B+ NK like CD8+ T cells an off target effect of bruton’s tyrosine kinase inhibitors in Waldenström macroglobulinemia
2025
Overview
Bruton’s tyrosine kinase inhibitors (BTKi), widely used in Waldenström macroglobulinemia (WM), are known to impair B cell function, but their broader immunological effects remain unclear. We investigated the T cell compartment in patients with WM receiving BTKi, including those who underwent a supervised treatment pause before a third COVID-19 mRNA vaccine dose, as well as treatment naïve controls. Using flow cytometry, antigen-specific T cell assays, and single-cell RNA sequencing, we found that BTKi-treated patients exhibited a reduction in naïve T cells, enrichment of terminal effector CD8⁺ T
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cells, and lower PD-1 expression. Despite poor vaccine-induced RBD-specific memory B cells, CD4⁺ and CD8⁺ T cell responses to SARS-CoV-2 remained detectable, with enhanced CD8⁺ responses to the omicron variant in BTKi-treated individuals. Single-cell transcriptomics revealed an expansion of CD16⁺ CD56⁺ Granzyme B⁺ NK-like CD8⁺ T cells in BTKi-treated patients, which further increased following BTKi interruption. These cells expressed a potent cytotoxic and NK-like transcriptional phenotype. Our findings identify a novel off-target effect of BTKi therapy: expansion of cytotoxic NK-like CD8⁺ T cells, with implications for immune monitoring and vaccine responsiveness in BTKi-treated patients.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors
/ Aged
/ Antigens
/ CD8-Positive T-Lymphocytes - drug effects
/ CD8-Positive T-Lymphocytes - immunology
/ CD8-Positive T-Lymphocytes - metabolism
/ COVID-19
/ COVID-19 - prevention & control
/ Female
/ Humanities and Social Sciences
/ Humans
/ Killer Cells, Natural - drug effects
/ Killer Cells, Natural - immunology
/ Killer Cells, Natural - metabolism
/ Kinases
/ Male
/ Patients
/ Peptides
/ Protein Kinase Inhibitors - pharmacology
/ Protein Kinase Inhibitors - therapeutic use
/ Science
/ Severe acute respiratory syndrome coronavirus 2
/ Vaccines
