Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
Leukemia. 2017 Dec;31(12):2678-2685. doi: 10.1038/leu.2017.146. Epub 2017 May 11.
A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.
骨髓老化的一个标志是脂肪细胞成分的增加，但这如何影响多发性骨髓瘤（MM）的发展尚不清楚。在这里，我们报告了脂肪因子瘦素作为调节不变自然杀伤 T（iNKT）细胞功能的主调节因子在抗骨髓瘤肿瘤免疫中的作用。我们观察到 MM 患者和 5T33 鼠 MM 模型中血清瘦素水平和 iNKT 细胞上瘦素受体（LR）表达明显增加。MM 细胞和瘦素协同拮抗了人和鼠 iNKT 细胞的抗肿瘤功能。体内阻断 LR 信号通路与 iNKT 刺激相结合可导致更好的抗肿瘤保护作用。这与重复 iNKT 细胞刺激时持续分泌 IFN-γ有关，并通过活体显微镜观察到动态抗原诱导的运动阻滞得到恢复，从而表明缓解了 iNKT 细胞失能。总的来说，我们的数据揭示了 LR 轴作为一种新的治疗靶点，用于检查点抑制以治疗 MM。
