Ando Ken, Fujita Hidetoshi, Hosoi Akihiro, Ma Liqiu, Wakatsuki Masaru, Seino Ken-Ichiro, Kakimi Kazuhiro, Imai Takashi, Shimokawa Takashi, Nakano Takashi
Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan.
Advanced Radiation Biology Research Program, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan.
J Radiat Res. 2017 Jul 1;58(4):446-455. doi: 10.1093/jrr/rrx005.
Carbon-ion radiotherapy (CIRT) is an advanced radiotherapy and has achieved good local control, even in tumors that are resistant to conventional photon beam radiotherapy (PBRT). However, distant metastasis control is an important issue. Recently, the combination of radiotherapy and immunotherapy has attracted the attention. In immunotherapy, dendritic cells (DCs) play a pivotal role in the anti-tumor immune system. However, the mechanisms underlying the combination therapy of DCs and radiotherapy have been unclear. In the present study, we evaluated anti-metastatic effects of this combination therapy, focused on the irradiation type and the route of DC administration, using a mouse model. C3H/He mice bearing NR-S1 cells were treated with CIRT or PBRT, using biologically equivalent doses. Subsequently, DCs were administered intratumorally (IT) or intravenously (IV). IV and IT DC administrations combined with CIRT to the local tumor, but not alone, significantly suppressed pulmonary metastasis, whereas the combination of DCs with PBRT suppressed metastasis at a relatively higher dose. Additionally, the anti-metastatic effect was greater in IV DC administration compared with in IT DC administration in both CIRT and PBRT. The expression levels of CD40 and IL-12 in DCs were significantly increased after co-culturing with CIRT-treated NR-S1 cells. In addition, IV administration of those co-cultured DCs significantly suppressed pulmonary metastasis. Furthermore, ecto-calreticulin levels from CIRT-treated NR-S1 cells significantly increased compared with those of a PBRT-treated tumor. Taken together, these results suggest that local CIRT combined with IV DCs augments an immunogenicity of the tumor cells by ecto-calreticulin expression and the maturation of DCs to stimulate anti-tumor immunity to decrease lung metastases.
碳离子放疗(CIRT)是一种先进的放疗方法,即使对于对传统光子束放疗(PBRT)耐药的肿瘤,也能实现良好的局部控制。然而,远处转移的控制是一个重要问题。最近,放疗与免疫疗法的联合应用引起了关注。在免疫疗法中,树突状细胞(DC)在抗肿瘤免疫系统中起着关键作用。然而,DC与放疗联合治疗的潜在机制尚不清楚。在本研究中,我们使用小鼠模型,聚焦于照射类型和DC给药途径,评估了这种联合治疗的抗转移效果。将携带NR-S1细胞的C3H/He小鼠用生物等效剂量的CIRT或PBRT进行治疗。随后,将DC瘤内注射(IT)或静脉注射(IV)。IV和IT DC给药与局部肿瘤的CIRT联合使用(而非单独使用)可显著抑制肺转移,而DC与PBRT联合使用在相对较高剂量时可抑制转移。此外,在CIRT和PBRT中,IV DC给药的抗转移效果均优于IT DC给药。与经CIRT处理的NR-S1细胞共培养后,DC中CD40和IL-12的表达水平显著升高。此外,静脉注射这些共培养的DC可显著抑制肺转移。此外,与PBRT治疗的肿瘤相比,经CIRT处理的NR-S1细胞的细胞外钙网蛋白水平显著升高。综上所述,这些结果表明,局部CIRT联合IV DC可通过细胞外钙网蛋白表达和DC成熟增强肿瘤细胞的免疫原性,从而刺激抗肿瘤免疫以减少肺转移。
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