肿瘤细胞治疗研究
英文原题：Peripheral CD8⁺ T-cell clonality and NK-cell expansion mark early response to mosunetuzumab in indolent B-cell lymphoma.
这些发现定义了mosunetuzumab治疗下的一种CD8+效应重塑状态，其特征为克隆扩增、选择性抑制性受体表达、胆固醇生物合成的持续激活以及与细胞因子相关的先天免疫机制参与，为支持T细胞功能和增强双特异性抗体疗效的潜在策略提供了框架。
Mosunetuzumab对多种B细胞淋巴瘤高度有效，但间歇给药CD20×CD3双特异性抗体所诱导的纵向免疫变化仍未被完全阐明。我们对一项2期临床试验（NCT04792502）中接受固定疗程（6个月）皮下注射mosunetuzumab治疗既往未经治疗的滤泡性淋巴瘤或边缘区淋巴瘤患者的外周血样本进行了免疫分析。分析包括流式细胞术、细胞因子谱分析，以及对分离的CD8+ T细胞进行RNA-seq并推断TCR repertoire。早期（第3周）治疗中样本显示广泛的细胞因子诱导、CD8+ T细胞重新分布，表现为TEMRA细胞减少和CD27+CD62L+过渡性效应记忆样细胞增加、PD-1和LAG-3表达升高，以及CD8+转录程序诱导，这些程序与活化、增殖、耗竭启动和SREBF2调控的胆固醇代谢一致。至治疗中期（第3个月），活化相关特征向基线收缩，未见表型耗竭证据，尽管RNA-seq显示LAG3、HAVCR2和LAYN持续过表达，以及SREBF2持续活化。与基线相比，治疗中期CD8+ T细胞克隆性增加，且更高的克隆性与早期临床完全缓解相关。Mosunetuzumab还诱导间接NK细胞活化和扩增，包括向CD56dimCD16bright效应状态偏移。NK细胞上HLA-DR上调与NK活化性血浆细胞因子的早期增加相关，且治疗中期较高的NK细胞计数与完全缓解相关。总之，这些发现定义了mosunetuzumab治疗下的一种CD8+效应重塑状态，其特征为克隆扩增、选择性抑制性受体表达、胆固醇生物合成的持续激活以及与细胞因子相关的先天免疫机制参与，为支持T细胞功能和增强双特异性抗体疗效的潜在策略提供了框架。
Mosunetuzumab is highly effective against many B-cell lymphomas, but longitudinal immune changes induced by intermittently dosed CD20×CD3 bispecific antibodies remain incompletely characterized. We performed immune profiling of peripheral blood samples from patients receiving fixed-duration (6 months) subcutaneous mosunetuzumab for previously untreated follicular or marginal zone lymphoma on a phase 2 clinical trial (NCT04792502). Analyses included flow cytometry, cytokine profiling, and RNA-seq of isolated CD8+ T-cells with TCR repertoire inference. Early (at 3 weeks) on-treatment samples showed broad cytokine induction, CD8+ T-cell redistribution with decreased TEMRA cells and increased CD27+CD62L+ transitional effector memory-like cells, increased PD-1 and LAG-3 expression, and induction of CD8+ transcriptional programs consistent with activation, proliferation, exhaustion priming, and SREBF2-regulated cholesterol metabolism. By mid-treatment (at 3 months), activation-associated features contracted toward baseline, with no evidence of phenotypic exhaustion, though with persistent overexpression of LAG3, HAVCR2, and LAYN on RNA-seq, as well as sustained SREBF2 activation. CD8+ T-cell clonality increased at mid-treatment compared with baseline and higher clonality was associated with early clinical complete response. Mosunetuzumab also induced indirect NK-cell activation and expansion, including skewing toward CD56dimCD16bright effector state. HLA-DR upregulation on NK cells correlated with early increases in NK-activating plasma cytokines, and higher NK-cell count at mid-treatment was associated with complete response. Together, these findings define a CD8+ effector-remodeling state on mosunetuzumab therapy, characterized by clonal expansion, selective inhibitory receptor expression, sustained activation of cholesterol biosynthesis, and cytokine-linked engagement of innate immune mechanisms, providing a framework for potential strategies to support T-cell function and enhance bispecific antibody efficacy.
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