Richter Silja, Böttcher Martin, Stoll Andrej, Zeremski Vanja, Völkl Simon, Mackensen Andreas, Ekici Arif B, Jacobs Benedikt, Mougiakakos Dimitrios
Department of Internal Medicine 5, Hematology and Clinical Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, Germany.
Department of Hematology and Oncology, Otto-von-Guericke-University Magdeburg University Hospital, Magdeburg, Germany; Health Campus of Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
Transplant Cell Ther. 2024 Jun;30(6):628.e1-628.e9. doi: 10.1016/j.jtct.2024.03.005. Epub 2024 Mar 7.
High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is a well-established treatment option for multiple myeloma and malignant lymphoma patients. It is able to induce long-term progression-free survival (PFS) in both patient groups and even provide a cure in patients with aggressive lymphoma. However, relapse is common and has been associated with the pace and quality of immunologic reconstitution after transplantation, as well as with immune cell exhaustion and immunometabolic defects. We aimed to analyze the dynamics of the prototypical exhaustion marker PD-1 on immune cells during reconstitution on high-dose chemotherapy followed by auto-SCT and its impact on PFS. We performed a comprehensive analysis of exhaustion and metabolic markers on immune cells from myeloma and lymphoma patients undergoing auto-SCT using flow cytometry and NanoString technologies. The expression levels of PD-1 were increased during early reconstitution after transplantation on T cells and natural killer (NK) cells, as well as on monocytes. However, while PD-1 expression in NK cells and monocytes normalized over time, PD-1 expression on T cells demonstrated a variable course. Of note, lymphoma patients with continuously increasing PD-1 expression on T cells after auto-SCT had an inferior median PFS of only 146 days, whereas the median PFS was not reached in the lymphoma patients without such a PD-1 expression pattern. T cells from patients with increased PD-1 expression after auto-SCT exhibited an immunometabolic (over)activation and exhausted phenotype compared to T cells from patients with a low PD-1 expression after transplantation, including higher levels of the glycolytic pacemaker enzyme hexokinase 2 and the inhibitory receptor CTLA-4. In addition, proliferating Ki-67 T cells were more abundant in patients with high PD-1 expression on T cells compared to those with low expression after auto-SCT (11.9% versus 4.2%). PD-1 expression on T cells might serve as an adverse biomarker for lymphoma patients undergoing auto-SCT; however, further validation by larger prospective studies is required.
大剂量化疗后进行自体干细胞移植（auto-SCT）是多发性骨髓瘤和恶性淋巴瘤患者一种成熟的治疗选择。它能够在这两类患者群体中诱导长期无进展生存（PFS），甚至能治愈侵袭性淋巴瘤患者。然而，复发很常见，且与移植后免疫重建的速度和质量、免疫细胞耗竭及免疫代谢缺陷有关。我们旨在分析大剂量化疗后进行auto-SCT免疫重建过程中免疫细胞上典型耗竭标志物程序性死亡受体1（PD-1）的动态变化及其对PFS的影响。我们使用流式细胞术和NanoString技术对接受auto-SCT的骨髓瘤和淋巴瘤患者免疫细胞上的耗竭及代谢标志物进行了全面分析。移植后早期免疫重建过程中，T细胞、自然杀伤（NK）细胞以及单核细胞上的PD-1表达水平均升高。然而，虽然NK细胞和单核细胞上的PD-1表达随时间恢复正常，但T细胞上的PD-1表达呈现出不同的变化过程。值得注意的是，auto-SCT后T细胞上PD-1表达持续增加的淋巴瘤患者，其无进展生存期（PFS）中位数仅为146天，情况较差，而没有这种PD-1表达模式的淋巴瘤患者未达到PFS中位数。与移植后PD-1表达低的患者的T细胞相比，auto-SCT后PD-1表达增加的患者的T细胞表现出免疫代谢（过度）激活和耗竭的表型，包括糖酵解关键酶己糖激酶2和抑制性受体细胞毒性T淋巴细胞相关蛋白4（CTLA-4）水平更高。此外，与auto-SCT后PD-1表达低的患者相比，T细胞上PD-1表达高的患者中增殖的Ki-67 T细胞更为丰富（11.9%对4.2%）。T细胞上的PD-1表达可能是接受auto-SCT的淋巴瘤患者的不良生物标志物；然而，需要更大规模的前瞻性研究进行进一步验证。
