T-cell Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of Immunotherapy.
T-cell Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of Immunotherapy.
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DOI：
10.1158/2326-6066.cir-15-0055
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发表时间：
2016-01
影响因子：
10.1
通讯作者：
Young JW
中科院分区：
文献类型：
--
作者：
Chung DJ;Pronschinske KB;Shyer JA;Sharma S;Leung S;Curran SA;Lesokhin AM;Devlin SM;Giralt SA;Young JW
多发性骨髓瘤是高剂量化疗和自体干细胞移植（ASCT）的最常见适应症，来那度胺维持治疗现在是移植后的标准。虽然来那度胺使无进展生存期增加一倍，但几乎所有患者最终都会复发。因此，移植后免疫治疗改善ASCT后的结果具有很大的优点，但首先需要描述免疫重建的动力学。我们评估了ASCT后淋巴细胞的组成和功能，以指导免疫治疗的最佳时机，并确定潜在的复发标志物。在ASCT后的早期淋巴细胞恢复期间，随着CD 8 + T细胞的扩增，调节性T细胞（TcB）下降，显著降低了Treg：CD 8+效应T细胞比率。这些CD 8 + T细胞可以早在移植后第+12天在体外对呈递肿瘤抗原的自体树突状细胞产生应答，成为抗原特异性溶细胞性T淋巴细胞效应子，从而证明细胞反应性的保留。在ASCT之前和之后，CD 4+和CD 8 + T细胞表达负调节分子CTLA-4、PD-1、LAG-3和TIM-3。然而，耗尽/衰老的CD 8 + T细胞亚群下调CD 28并上调CD 57和PD-1，表征ASCT后的免疫损伤和复发。复发患者在移植后+3个月，但在检测到临床疾病之前，这些细胞的数量较高，表明它们在识别复发风险较高的患者方面的适用性。PD-1阻断还在体外恢复低应答、耗竭/衰老的CD 8 + T细胞的增殖和细胞因子分泌。总的来说，这些结果将T细胞耗竭/衰老确定为复发的显著特征，并支持在ASCT后早期引入免疫疗法以刺激抗肿瘤免疫。
Multiple myeloma is the most common indication for high-dose chemotherapy and autologous stem cell transplantation (ASCT), and lenalidomide maintenance post-transplant is now standard. Although lenalidomide doubles progression-free survival, almost all patients eventually relapse. Post-transplant immunotherapy to improve outcomes after ASCT therefore has great merit but first requires delineation of the dynamics of immune reconstitution. We evaluated lymphocyte composition and function after ASCT to guide optimal timing of immunotherapy and to identify potential markers of relapse. Regulatory T cells (Tregs) decline as CD8+ T cells expand during early lymphocyte recovery after ASCT, markedly reducing the Treg:CD8+ effector T-cell ratio. These CD8+ T cells can respond to autologous dendritic cells presenting tumor antigen in vitro as early as day +12 post-transplant, becoming antigen-specific cytolytic T-lymphocyte effectors and thereby demonstrating preservation of cellular reactivity. CD4+ and CD8+ T cells express the negative regulatory molecules, CTLA-4, PD-1, LAG-3, and TIM-3, before and after ASCT. A subpopulation of exhausted/senescent CD8+ T cells, however, down-regulates CD28 and up-regulates CD57 and PD-1, characterizing immune impairment and relapse after ASCT. Relapsing patients have higher numbers of these cells at +3 months after transplant, but before detection of clinical disease, indicating their applicability in identifying patients at higher risk of relapse. PD-1 blockade also revives the proliferation and cytokine secretion of the hyporesponsive, exhausted/senescent CD8+ T cells in vitro. Collectively, these results identify T cell exhaustion/senescence as a distinguishing feature of relapse and support early introduction of immunotherapy to stimulate antitumor immunity after ASCT.