Görgün Güllü, Samur Mehmet K, Cowens Kristen B, Paula Steven, Bianchi Giada, Anderson Julie E, White Randie E, Singh Ahaana, Ohguchi Hiroto, Suzuki Rikio, Kikuchi Shohei, Harada Takeshi, Hideshima Teru, Tai Yu-Tzu, Laubach Jacob P, Raje Noopur, Magrangeas Florence, Minvielle Stephane, Avet-Loiseau Herve, Munshi Nikhil C, Dorfman David M, Richardson Paul G, Anderson Kenneth C
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Biostatistics and Computational Biology, Harvard School of Public Health, Boston, Massachusetts.
Clin Cancer Res. 2015 Oct 15;21(20):4607-18. doi: 10.1158/1078-0432.CCR-15-0200. Epub 2015 May 15.
PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell-mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu.
Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138(+) multiple myeloma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myeloma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on autologous anti-multiple myeloma immune response and tumor cell growth.
Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNγ and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalidomide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression.
Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti-multiple myeloma immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy.
PD-1/PD-L1信号通路在促进肿瘤生长的同时抑制效应细胞介导的抗肿瘤免疫反应。在此，我们评估了单独或联合来那度胺对PD-1/PD-L1进行单药阻断和双药阻断，对辅助细胞和免疫细胞功能以及骨髓（BM）环境中多发性骨髓瘤细胞生长的影响。
在新诊断（ND）多发性骨髓瘤、复发/难治性（RR）多发性骨髓瘤患者与健康供者（HD）的骨髓中，测定免疫效应细胞上PD-1的表面表达，以及CD138(+)多发性骨髓瘤细胞和髓系来源抑制细胞（MDSC）上PD-L1的表达。我们确定了单独或联合来那度胺对PD-1/PD-L1进行单药阻断和双药阻断，对自体抗多发性骨髓瘤免疫反应和肿瘤细胞生长的影响。
与HD相比，ND和RR患者的多发性骨髓瘤细胞PD-L1 mRNA和表面表达均增加。多发性骨髓瘤效应细胞上PD-1的表达也显著增加。重要的是，PD-1/PD-L1阻断可消除骨髓基质细胞（BMSC）诱导的多发性骨髓瘤生长，PD-1/PD-L1与来那度胺联合阻断可进一步抑制BMSC诱导的肿瘤生长。这些效应与效应细胞中IFNγ和颗粒酶B细胞内表达的诱导有关。重要的是，多发性骨髓瘤中MDSC上的PD-L1表达高于抗原呈递细胞，PD-1/PD-L1阻断可抑制MDSC介导的多发性骨髓瘤生长。最后，来那度胺联合PD-1/PD-L1阻断可抑制MDSC介导的免疫抑制。
因此，我们的数据表明，检查点信号通路在提供多发性骨髓瘤促进肿瘤生长、免疫抑制的微环境中起重要作用，并且PD-1/PD-L1阻断可诱导抗多发性骨髓瘤免疫反应，来那度胺可增强这种反应，为联合治疗的临床评估提供了框架。
