Yokota Chisato, Nakata Jun, Takano Koji, Nakajima Hiroko, Hayashibara Hiromu, Minagawa Hikaru, Chiba Yasuyoshi, Hirayama Ryuichi, Kijima Noriyuki, Kinoshita Manabu, Hashii Yoshiko, Tsuboi Akihiro, Oka Yoshihiro, Oji Yusuke, Kumanogoh Atsushi, Sugiyama Haruo, Kagawa Naoki, Kishima Haruhiko
Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Neurooncol Adv. 2021 Jun 29;3(1):vdab091. doi: 10.1093/noajnl/vdab091. eCollection 2021 Jan-Dec.
Wilms' tumor gene 1 (WT1) peptide vaccine and anti-programmed cell death-1 (anti-PD-1) antibody are expected as immunotherapies to improve the clinical outcome of glioblastoma. The aims of this study were to clarify how each immunotherapy affects tumor-infiltrating immune cells (TIIs) and to determine whether the combination of these two therapies could synergistically work.
Mice were transplanted with WT1 and programmed cell death-ligand 1 doubly expressing glioblastoma cells into brain followed by treatment with WT1 peptide vaccine, anti-PD-1 antibody, or the combination of the two, and survival of each therapy was compared. CD45 cells were positively selected as TIIs from the brains with tumors, and TIIs were compared between WT1 peptide vaccine and anti-PD-1 antibody therapies.
Most mice seemed to be cured by the combination therapy with WT1 peptide vaccine and anti-PD-1 antibody, which was much better survival than each monotherapy. A large number of CD4 T cells, CD8 T cells, and NK cells including WT1-specific CD8 and CD4 T cells infiltrated into the glioblastoma in WT1 peptide vaccine-treated mice. On the other hand, the number of TIIs did not increase, but instead PD-1 molecule expression was decreased on the majority of the tumor-infiltrating CD8 T cells in the anti-PD-1 antibody-treated mice.
Our results clearly demonstrated that WT1 peptide vaccine and anti-PD-1 antibody therapies worked in the different steps of cancer-immunity cycle and that the combination of the two therapies could work synergistically against glioblastoma.
肾母细胞瘤基因1（WT1）肽疫苗和抗程序性细胞死亡蛋白1（抗PD-1）抗体有望作为免疫疗法改善胶质母细胞瘤的临床结局。本研究的目的是阐明每种免疫疗法如何影响肿瘤浸润免疫细胞（TIIs），并确定这两种疗法的联合使用是否具有协同作用。
将WT1和程序性细胞死亡配体1双表达的胶质母细胞瘤细胞移植到小鼠脑内，随后分别用WT1肽疫苗、抗PD-1抗体或两者联合进行治疗，并比较每种疗法的生存期。从有肿瘤的小鼠脑中阳性选择CD45细胞作为TIIs，并比较WT1肽疫苗和抗PD-1抗体疗法中的TIIs。
大多数小鼠似乎通过WT1肽疫苗和抗PD-1抗体联合治疗得以治愈，联合治疗的生存期比每种单一疗法都要好得多。在接受WT1肽疫苗治疗的小鼠中，大量CD4 T细胞、CD8 T细胞和NK细胞（包括WT1特异性CD8和CD4 T细胞）浸润到胶质母细胞瘤中。另一方面，在接受抗PD-1抗体治疗的小鼠中，TIIs数量没有增加，而是大多数肿瘤浸润CD8 T细胞上的PD-1分子表达下降。
我们的结果清楚地表明，WT1肽疫苗和抗PD-1抗体疗法在癌症免疫循环的不同步骤中发挥作用，并且这两种疗法联合使用可对胶质母细胞瘤产生协同作用。
