Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
J Immunol. 2020 Nov 1;205(9):2519-2531. doi: 10.4049/jimmunol.2000487. Epub 2020 Sep 18.
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.
越来越多的证据表明，局部低分割放疗（LRT）可以引发免疫原性和免疫抑制性的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效应并诱导远隔效应。在这项研究中，我们发现非消融性低分割照射后间皮瘤肿瘤微环境中 Foxp3 调节性 T 细胞（Tregs）的上调显著限制了照射的成功。使用 DEREG 小鼠，通过白喉毒素注射可以对 Foxp3 Tregs 进行条件性和有效的耗竭，我们观察到非消融性低分割照射后瞬时 Foxp3 Treg 耗竭提供了协同的局部控制，并使 T 细胞库偏向中央和效应记忆 T 细胞，从而导致长期治愈。此外，这种组合疗法通过全身激活细胞毒性 T 细胞和增强 IFN-γ和颗粒酶 B 的产生，在同时发生的间皮瘤模型中对未照射的肿瘤显示出显著的远隔效应。尽管非消融性照射的一个分数保留了局部控制，但需要三个分数才能产生远隔效应。在照射和未照射的肿瘤中，肿瘤浸润性 CD4 和 CD8 T 细胞上调了 PD-1 和 CTLA-4，这表明免疫检查点抑制剂在 LRT 和 Foxp3 Treg 耗竭后可能有益。我们的发现适用于免疫放射治疗策略，以在临床环境中产生最佳的抗肿瘤免疫反应。在短疗程照射后立即靶向 Tregs 可能对照射的局部反应及其远隔效应产生重大影响。
