Eckert Franziska, Jelas Ivan, Oehme Moritz, Huber Stephan M, Sonntag Katja, Welker Christian, Gillies Stephen D, Strittmatter Wolfgang, Zips Daniel, Handgretinger Rupert, Schilbach Karin
Department of Radiation Oncology, Eberhard Karls University Tübingen, Tübingen, Germany.
Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Tübingen, Germany.
Oncoimmunology. 2017 Apr 28;6(6):e1323161. doi: 10.1080/2162402X.2017.1323161. eCollection 2017.
NHS-IL12 is an immunocytokine, a fusion protein of IL12's functional domains and a necrosis-targeting antibody, which has shown significant effects against human rhabdomyosarcoma xenografts in a humanized tumor model, including terminal growth arrest and differentiation of the tumor cells. Here, we locally irradiated the tumors, increasing necrosis and consequently intratumoral immune cytokine availability, and asked whether this effect may surmount efficacy of single treatment modality. Humanized mice bearing bilateral rhabdomyosarcoma xenografts were evaluated for tumor burden and survival after irradiation, systemic NHS-IL12 therapy or a combination of both. Intratumoral immune compartments were characterized by immunohistochemistry and molecular methods. T1-cytokine dependency of underlying effector mechanisms were investigated in several human tumor cell lines. NHS-IL12 when combined with irradiation terminally arrested tumor growth and significantly improved survival. Combination treatment induced dense intratumoral T-cell infiltrates, clonal epitope-specific T-cell expansions, expression of cytotoxins, decreased pro-tumorigenic cytokines and induced senescence and differentiation in the cancer cells. Senescence and differentiation were reproduced and confirmed to be dependent on T1 cytokines IFNγ and TNF-α. NHS-IL12 and irradiation together induced broad intratumoral T1 biased NK and T-cell compartments, established antitumoral cytokine profiles and irreversibly growth arrested tumor cells, leading to systemic cancer control and improved survival. For the first time, we describe immune-induced senescence as a novel mechanism resulting from a treatment regimen combining irradiation with immunotherapy.
NHS-IL12是一种免疫细胞因子，是白细胞介素12（IL12）功能域与靶向坏死的抗体的融合蛋白，在人源化肿瘤模型中已显示出对人横纹肌肉瘤异种移植瘤有显著效果，包括肿瘤细胞的终末生长停滞和分化。在此，我们对肿瘤进行局部照射，增加坏死从而提高肿瘤内免疫细胞因子的可用性，并探究这种效应是否能超越单一治疗方式的疗效。对双侧携带横纹肌肉瘤异种移植瘤的人源化小鼠在照射、全身NHS-IL12治疗或两者联合治疗后评估肿瘤负荷和生存期。通过免疫组织化学和分子方法对肿瘤内免疫区室进行表征。在几种人肿瘤细胞系中研究了潜在效应机制的T1细胞因子依赖性。NHS-IL12与照射联合使用时可使肿瘤生长终末停滞并显著提高生存期。联合治疗诱导肿瘤内密集的T细胞浸润、克隆表位特异性T细胞扩增、细胞毒素表达、促肿瘤细胞因子减少，并诱导癌细胞衰老和分化。衰老和分化得以重现并证实依赖于T1细胞因子干扰素γ（IFNγ）和肿瘤坏死因子-α（TNF-α）。NHS-IL12与照射共同诱导肿瘤内广泛的T1偏向性自然杀伤细胞和T细胞区室，建立抗肿瘤细胞因子谱并使肿瘤细胞生长不可逆地停滞，从而实现全身性癌症控制并提高生存期。我们首次将免疫诱导的衰老描述为一种由照射与免疫疗法联合的治疗方案产生的新机制。
