Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells.
Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells.
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DOI：
10.1097/cji.0b013e3181b88ffc
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Restifo NP
中科院分区：
文献类型：
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作者：
Wrzesinski C;Paulos CM;Kaiser A;Muranski P;Palmer DC;Gattinoni L;Yu Z;Rosenberg SA;Restifo NP
过继性细胞转移（ACT）免疫治疗前的细胞耗竭可通过增强先天免疫、增加体内平衡细胞因子的获得以及抑制调节性T细胞和骨髓源性抑制细胞的数量来增强抗肿瘤应答。虽然很明显，高剂量全身照射（HD-TBI）与造血干细胞（HSC）移植一起给予有效地提高ACT，淋巴细胞耗竭的强度和肿瘤治疗效果之间的关系还没有系统的研究。使用自身/肿瘤反应性CD 8 + T细胞的pmel-1小鼠模型，我们使用线性回归分析观察到预处理方案的强度与基于ACT的治疗的功效之间的强相关性。这是作为单剂量（R2 = 0.97，p < 0.001）或分次剂量（R2 = 0.94，p < 0.001）施用的制备型TBI的情况。制备性TBI量的增加与转移的肿瘤反应性CD 8 + T细胞对具有抑制活性潜力的内源性细胞的逐渐更有利的比率直接相关，所述内源性细胞包括：（潜在的T调节细胞）; Gr 1+细胞（其能够作为髓源性抑制细胞发挥功能）：以及内源性CD 8+和NK1.1+细胞（其可在消融后环境中充当稳态细胞因子的“库”）。随着消融的增加，我们还观察到血清中LPS水平升高和全身炎性细胞因子水平升高。因此，增加强度淋巴细胞耗竭触发增强的肿瘤治疗功效，并且HD-TBI的益处必须针对其风险进行滴定。
Lymphodepletion prior to adoptive cell transfer (ACT)-based immunotherapies can enhance anti-tumor responses by augmenting innate immunity, by increasing access to homeostatic cytokines, and by depressing the numbers of regulatory T cells and myeloid-derived suppressor cells. Although it is clear that high-dose total body irradiation (HD-TBI) given together with hematopoietic stem cell (HSC) transplantation effectively enhances ACT, the relationship between the intensity of lymphodepletion and tumor treatment efficacy has not been systematically studied. Using the pmel-1 mouse model of self/tumor-reactive CD8+ T cells, we observed a strong correlation between the intensity of the conditioning regimen and the efficacy of ACT-based treatments using linear regression analysis. This was the case for preparative TBI administered either as a single dose (R2 = 0.97, p < 0.001) or in fractionated doses (R2 = 0.94, p < 0.001). Increased amounts of preparative TBI were directly correlated with progressively more favorable ratios of transferred tumor-reactive CD8+ T cells towards endogenous cells with the potential for inhibitory activity including: CD4+ cells (potentially T regulatory cells); Gr1+ cells (which are capable of functioning as myeloid-derived suppressor cells): and endogenous CD8+ and NK1.1+ cells (that can act as “sinks” for homeostatic cytokines in the post-ablative setting). With increasing ablation, we also observed elevated LPS levels in the sera and heightened levels of systemic inflammatory cytokines. Thus, increased intensity lymphodepletion triggers enhanced tumor treatment efficacy and the benefits of HD-TBI must be titrated against its risks.