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Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-09-18 , DOI: 10.4049/jimmunol.2000487
Mikihiro Kohno 1 , Junichi Murakami 1 , Licun Wu 1 , Mei-Lin Chan 1 , Zhihong Yun 1 , B C John Cho 2 , Marc de Perrot 3, 4, 5
Affiliation  

Key Points Tregs rapidly rise in the tumor microenvironment after nonablative irradiation. Transient Treg depletion increases the efficiency of nonablative irradiation. Treg depletion after three fractions of radiation induces systemic antitumor immunity. Increasing evidence indicates that local hypofractionated radiotherapy (LRT) can elicit both immunogenic and immunosuppressive local and systemic immune responses. We thus hypothesized that blockade of LRT-induced immunosuppressive responses could augment the antitumor effects and induce an abscopal response. In this study, we found that the upregulation of Foxp3+ regulatory T cells (Tregs) in the mesothelioma tumor microenvironment after nonablative oligofractionated irradiation significantly limited the success of irradiation. Using DEREG mice, which allow conditional and efficient depletion of Foxp3+ Tregs by diphtheria toxin injection, we observed that transient Foxp3+ Treg depletion immediately after nonablative oligofractionated irradiation provided synergistic local control and biased the T cell repertoire toward central and effector memory T cells, resulting in long-term cure. Furthermore, this combination therapy showed significant abscopal effect on the nonirradiated tumors in a concomitant model of mesothelioma through systemic activation of cytotoxic T cells and enhanced production of IFN-γ and granzyme B. Although local control was preserved with one fraction of nonablative irradiation, three fractions were required to generate the abscopal effect. PD-1 and CTLA-4 were upregulated on tumor-infiltrating CD4+ and CD8+ T cells in irradiated and nonirradiated tumors, suggesting that immune checkpoint inhibitors could be beneficial after LRT and Foxp3+ Treg depletion. Our findings are applicable to the strategy of immuno-radiotherapy for generating optimal antitumor immune responses in the clinical setting. Targeting Tregs immediately after a short course of irradiation could have a major impact on the local response to irradiation and its abscopal effect.

中文翻译:

Foxp3+ 调节性 T 细胞耗竭在非消融性寡分割照射后增强了鼠恶性间皮瘤的远侧效应

关键点 非消融照射后,Tregs 在肿瘤微环境中迅速上升。瞬时 Treg 耗竭增加了非烧蚀照射的效率。三部分辐射后 Treg 耗竭诱导全身抗肿瘤免疫。越来越多的证据表明,局部大分割放疗 (LRT) 可以引发免疫原性和免疫抑制性局部和全身免疫反应。因此,我们假设阻断 LRT 诱导的免疫抑制反应可以增强抗肿瘤作用并诱导远隔反应。在这项研究中,我们发现非消融性寡分割照射后间皮瘤肿瘤微环境中 Foxp3+ 调节性 T 细胞 (Tregs) 的上调显着限制了照射的成功。使用 DEREG 小鼠,允许通过白喉毒素注射有条件和有效地消耗 Foxp3+ Treg,我们观察到在非消融性寡分割照射后立即短暂的 Foxp3+ Treg 消耗提供了协同局部控制并使 T 细胞库偏向中枢和效应记忆 T 细胞,导致长期治愈. 此外,这种联合疗法通过系统性激活细胞毒性 T 细胞和增强 IFN-γ 和颗粒酶 B 的产生,对伴随的间皮瘤模型中的未照射肿瘤显示出显着的远隔效应。需要分数来产生远隔效应。PD-1 和 CTLA-4 在受照射和未受照射肿瘤中肿瘤浸润的 CD4+ 和 CD8+ T 细胞上上调,表明免疫检查点抑制剂在 LRT 和 Foxp3+ Treg 耗竭后可能有益。我们的研究结果适用于在临床环境中产生最佳抗肿瘤免疫反应的免疫放射治疗策略。在短期照射后立即靶向 Treg 可能对局部照射反应及其远隔效应产生重大影响。
更新日期:2020-09-18
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