Ito Fumito, Li Qiao, Shreiner Andrew B, Okuyama Ryuji, Jure-Kunkel Maria N, Teitz-Tennenbaum Seagal, Chang Alfred E
Division of Surgical Oncology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Cancer Res. 2004 Nov 15;64(22):8411-9. doi: 10.1158/0008-5472.CAN-04-0590.
In weakly and poorly immunogenic tumor models, we examined the effects of stimulating CD137 (4-1BB) in vivo by administering anti-CD137 monoclonal antibody after tumor lysate-pulsed dendritic cell (TP-DC) vaccination. TP-DC subcutaneous vaccination induced a transient up-regulation of CD137 on T cells and natural killer (NK) cells within vaccine-primed lymph nodes (VPLNs). In established pulmonary and subcutaneous tumor models, anti-CD137 synergistically enhanced tumor regression after TP-DC vaccination. In the subcutaneous tumor model, the combined therapy resulted in improved survival. Combined therapy also resulted in improved local control of subcutaneous tumor after surgical resection. Anti-CD137 polarized the cytokine release of VPLNs and spleen cells in response to tumor antigen toward a type 1 (interferon-gamma) versus a type 2 (interleukin-4) profile. Cell depletion and the use of knockout animals identified that CD8(+), CD4(+), and NK cells were involved in the tumor rejection response and that CD8(+) cells had the major effector role. Anti-CD137 administration resulted in increased proliferation of adoptively transferred OT-1 CD8(+) T cells in the VPLNs of mice inoculated with B16-OVA TP-DCs. Polarization toward type 1 (interferon-gamma) versus type 2 (interleukin-4) was also observed with the OT-1 cells from VPLNs and spleen cells after anti-CD137 injections. This polarization effect was abrogated by the in vivo depletion of NK cells. These findings indicate that the adjuvant effect of anti-CD137 given in conjunction with TP-DC vaccination is associated with the polarization of T effector cells toward a type 1 response to tumor antigen and is mediated via NK cells.
在免疫原性较弱和较差的肿瘤模型中，我们通过在肿瘤裂解物脉冲树突状细胞（TP-DC）疫苗接种后给予抗CD137单克隆抗体，研究了体内刺激CD137（4-1BB）的效果。TP-DC皮下接种疫苗可诱导疫苗致敏淋巴结（VPLN）内T细胞和自然杀伤（NK）细胞上CD137的短暂上调。在已建立的肺部和皮下肿瘤模型中，抗CD137在TP-DC疫苗接种后协同增强肿瘤消退。在皮下肿瘤模型中，联合治疗可提高生存率。联合治疗还可改善手术切除后皮下肿瘤的局部控制。抗CD137使VPLN和脾细胞针对肿瘤抗原的细胞因子释放朝着1型（干扰素-γ）而非2型（白细胞介素-4）方向极化。细胞清除实验和基因敲除动物实验表明，CD8(+)、CD4(+)和NK细胞参与了肿瘤排斥反应，且CD8(+)细胞起主要效应作用。给予抗CD137可导致接种B16-OVA TP-DC的小鼠VPLN中过继转移的OT-1 CD8(+) T细胞增殖增加。抗CD137注射后，VPLN和脾细胞中的OT-1细胞也观察到朝着1型（干扰素-γ）而非2型（白细胞介素-4）方向极化。体内清除NK细胞可消除这种极化效应。这些发现表明，与TP-DC疫苗接种联合使用时，抗CD137的佐剂效应与T效应细胞朝着对肿瘤抗原的1型反应极化有关，并通过NK细胞介导。
