Eldershaw S, Verma K, Croft W, Rai T, Kinsella F A M, Stephens C, Chen H, Nunnick J, Zuo J, Malladi R, Moss P
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
Centre for Computational Biology, University of Birmingham, Birmingham, UK.
iScience. 2021 Feb 7;24(3):102164. doi: 10.1016/j.isci.2021.102164. eCollection 2021 Mar 19.
Chemotherapy pre-conditioning is an essential component of chimeric antigen receptor transduced cell therapy. Acute lymphopenia-induced proliferation (LIP) is known to be driven primarily by homeostatic cytokines, but little is known on the underlying mechanisms in humans. We undertook phenotypic and transcriptional analysis of T cells undergoing LIP two weeks post-myeloablative autograft stem cell transplantation. Strong IL-7 signaling was reflected in downregulated IL-7R expression on all T cells, including naive cells, along with parallel increased IL-2Rα expression. Notably, activated residual naive cells expressed Fas indicating recent TCR engagement. Moreover, proportion of Ki67 + FoxP3+ Tregs was almost doubled. Transcriptional analysis revealed increased fatty acid metabolism and interferon signaling responses. In contrast, TGF-β signaling was strongly suppressed. Thus, human LIP response is characterized by cytokine and TCR-driven proliferation which drives global T cell activation but also preferentially triggers regulatory cell expansion which may limit tumor-specific immunity. These features indicate potential therapeutic opportunities to manipulate immunotherapy regimens incorporating LIP conditioning protocols.
化疗预处理是嵌合抗原受体转导细胞疗法的重要组成部分。急性淋巴细胞减少诱导增殖（LIP）主要由稳态细胞因子驱动，但人类潜在机制尚不清楚。我们对清髓性自体造血干细胞移植两周后经历LIP的T细胞进行了表型和转录分析。强烈的IL-7信号反映在所有T细胞（包括幼稚细胞）上IL-7R表达下调，同时IL-2Rα表达平行增加。值得注意的是，活化的残留幼稚细胞表达Fas，表明近期TCR参与。此外，Ki67 + FoxP3 + Tregs的比例几乎翻倍。转录分析显示脂肪酸代谢和干扰素信号反应增加。相比之下，TGF-β信号被强烈抑制。因此，人类LIP反应的特征是细胞因子和TCR驱动的增殖，这驱动了整体T细胞活化，但也优先触发调节性细胞扩增，这可能会限制肿瘤特异性免疫。这些特征表明了操纵包含LIP预处理方案的免疫治疗方案的潜在治疗机会。
