De Martino Mara, Daviaud Camille, Lira María Cecilia, Hernandez-Zirofsky Kayla, Vanpouille-Box Claire
Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.
Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, 10065, New York, NY, USA.
Cancer Lett. 2025 Sep 28;628:217856. doi: 10.1016/j.canlet.2025.217856. Epub 2025 Jun 6.
Radiation therapy (RT) can release pro-inflammatory signals to jumpstart an anti-tumor immune response. However, glioblastoma (GBM) often recurs, suggesting that RT might not act as an immune adjuvant in this disease. A possible explanation for the lack of immune stimulation is the use of irradiation regimens that do not effectively stimulate anti-tumor immunity against GBM. Here, we tested the ability of various RT schedules to elicit type I interferon (IFN-I) response and explored its synergy with immunotherapy (IT) to trigger anti-tumor immunity against GBM. Using three murine GBM models, we show in vitro that single dose radiation ranging from 0Gy to 20Gy and fractionated radiation schedules (i.e. 3 daily fractions of 8Gy; 3 × 8Gy and 5 daily fractions of 6Gy; 5 × 6Gy) accumulates double stranded DNA and release IFN-I related cytokines in a dose-dependent fashion; with fractionated schedules being superior in triggering cancer-cell intrinsic IFN-I responses. Side-by-side comparison of various radiation regimen in vivo revealed that 5 × 6Gy better control GBM across the three GBM models tested. However, the addition of anti-PD1 or anti-CTLA4 to an immunogenic radiation schedule (i.e. 5 × 6Gy) did not prolong survival of irradiated mice. Surprisingly, only the dual blockade of PD-1 and CTLA4 promoted the expansion of proliferative T cells and conveyed immunological memory against irradiated GBM. Overall, this study demonstrates that an immunogenic radiation regimen is not sufficient to mount an anti-tumor immune response when combine with IT as monotherapy and highlights the need to combine an immunogenic irradiation with multiple IT to overcome immunosuppression of GBM.
放射治疗（RT）可释放促炎信号以启动抗肿瘤免疫反应。然而，胶质母细胞瘤（GBM）常复发，这表明RT在这种疾病中可能无法作为免疫佐剂。缺乏免疫刺激的一个可能解释是使用的照射方案不能有效刺激针对GBM的抗肿瘤免疫。在此，我们测试了各种RT方案引发I型干扰素（IFN-I）反应的能力，并探索了其与免疫疗法（IT）协同触发针对GBM的抗肿瘤免疫的作用。使用三种小鼠GBM模型，我们在体外表明，0Gy至20Gy的单剂量辐射和分割辐射方案（即每天3次，每次8Gy；3×8Gy和每天5次，每次6Gy；5×6Gy）以剂量依赖性方式积累双链DNA并释放IFN-I相关细胞因子；分割方案在触发癌细胞内在的IFN-I反应方面更具优势。体内各种辐射方案的并排比较显示，在测试的三种GBM模型中，5×6Gy能更好地控制GBM。然而，在免疫原性辐射方案（即5×6Gy）中添加抗PD1或抗CTLA4并不能延长受照射小鼠的生存期。令人惊讶的是，只有同时阻断PD-1和CTLA4才能促进增殖性T细胞的扩增并传递针对受照射GBM的免疫记忆。总体而言，本研究表明，免疫原性辐射方案与IT联合作为单一疗法时不足以引发抗肿瘤免疫反应，并强调需要将免疫原性照射与多种IT联合以克服GBM的免疫抑制。
