Laboratory of Cellular Immunobiology, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. The Rockefeller University, New York, New York. Weill Cornell Medical College, New York, New York.
Laboratory of Cellular Immunobiology, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Immunol Res. 2016 Jan;4(1):61-71. doi: 10.1158/2326-6066.CIR-15-0055. Epub 2015 Oct 13.
Multiple myeloma is the most common indication for high-dose chemotherapy and autologous stem cell transplantation (ASCT), and lenalidomide maintenance after transplant is now standard. Although lenalidomide doubles progression-free survival, almost all patients eventually relapse. Posttransplant 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 (Treg) 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 after 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, downregulates CD28 and upregulates 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.
多发性骨髓瘤是高剂量化疗和自体干细胞移植（ASCT）的最常见适应证，移植后接受来那度胺维持治疗现在已是标准疗法。虽然来那度胺使无进展生存期翻倍，但几乎所有患者最终都会复发。因此，移植后免疫治疗以改善 ASCT 后的结果具有重要意义，但首先需要明确免疫重建的动态。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，并确定复发的潜在标志物。调节性 T 细胞（Treg）在 ASCT 后早期淋巴细胞恢复期间随着 CD8+T 细胞的扩增而下降，显著降低了 Treg:CD8+效应 T 细胞的比值。这些 CD8+T 细胞早在移植后第 12 天就可以对自体树突状细胞呈递的肿瘤抗原产生反应，成为抗原特异性细胞毒性 T 淋巴细胞效应物，从而表现出细胞反应性的保留。CD4+和 CD8+T 细胞在 ASCT 前后均表达负调节分子 CTLA-4、PD-1、LAG-3 和 TIM-3。然而，耗尽/衰老的 CD8+T 细胞的一个亚群下调 CD28 并上调 CD57 和 PD-1，这表明移植后存在免疫受损和复发。复发患者在移植后 3 个月时这些细胞数量更高，但在检测到临床疾病之前，这表明它们可用于识别复发风险较高的患者。PD-1 阻断剂也可恢复体外低反应性、耗尽/衰老的 CD8+T 细胞的增殖和细胞因子分泌。总之，这些结果表明 T 细胞耗竭/衰老可作为复发的一个特征，并支持在 ASCT 后早期引入免疫疗法以刺激抗肿瘤免疫。
