肿瘤细胞治疗研究
英文原题：Expanded CD16(+)CD56(+)Granzyme B(+) NK like CD8(+) T cells an off target effect of bruton's tyrosine kinase inhibitors in Waldenström macroglobulinemia.
Expanded CD16(+)CD56(+)Granzyme B(+) NK like CD8(+) T cells an off target effect of bruton's tyrosine kinase inhibitors in Waldenström macroglobulinemia.
Bruton酪氨酸激酶抑制剂（BTKi）广泛用于华氏巨球蛋白血症（WM），已知会损害B细胞功能，但其更广泛的免疫学效应仍不清楚。
Bruton酪氨酸激酶抑制剂（BTKi）广泛用于华氏巨球蛋白血症（WM），已知会损害B细胞功能，但其更广泛的免疫学效应仍不清楚。我们研究了接受BTKi治疗的WM患者的T细胞区室，包括在接种第三剂COVID-19 mRNA疫苗前经过监督下治疗暂停的患者，以及未经治疗的对照组。利用流式细胞术、抗原特异性T细胞检测和单细胞RNA测序，我们发现接受BTKi治疗的患者表现为初始T细胞减少、终末效应CD8⁺ T emra细胞富集以及PD-1表达降低。尽管疫苗诱导的RBD特异性记忆B细胞较差，但对SARS-CoV-2的CD4⁺和CD8⁺ T细胞反应仍可检测到，且在接受BTKi治疗的个体中对omicron变异株的CD8⁺反应增强。单细胞转录组学揭示，在接受BTKi治疗的患者中CD16⁺ CD56⁺ Granzyme B⁺ NK样CD8⁺ T细胞扩增，且在BTKi中断后进一步增加。这些细胞表达强效细胞毒性和NK样转录表型。我们的发现确定了BTKi治疗的一种新的脱靶效应：细胞毒性NK样CD8⁺ T细胞扩增，这对接受BTKi治疗患者的免疫监测和疫苗反应性具有重要意义。
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 emra 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.
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