Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Int J Mol Sci. 2021 Nov 14;22(22):12295. doi: 10.3390/ijms222212295.
The unprecedented successes of immunotherapies (IOs) including immune checkpoint blockers (ICBs) and adoptive T-cell therapy (ACT) in patients with late-stage cancer provide proof-of-principle evidence that harnessing the immune system, in particular T cells, can be an effective approach to eradicate cancer. This instills strong interests in understanding the immunomodulatory effects of radiotherapy (RT), an area that was actually investigated more than a century ago but had been largely ignored for many decades. With the "newly" discovered immunogenic responses from RT, numerous endeavors have been undertaken to combine RT with IOs, in order to bolster anti-tumor immunity. However, the underlying mechanisms are not well defined, which is a subject of much investigation. We therefore conducted a systematic literature search on the molecular underpinnings of RT-induced immunomodulation and IOs, which identified the IFN-JAK-STAT pathway as a major regulator. Our further analysis of relevant studies revealed that the signaling strength and duration of this pathway in response to RT and IOs may determine eventual immunological outcomes. We propose that strategic targeting of this axis can boost the immunostimulatory effects of RT and radiosensitizing effects of IOs, thereby promoting the efficacy of combination therapy of RT and IOs.
免疫疗法（IOs）包括免疫检查点抑制剂（ICBs）和过继性 T 细胞疗法（ACT）在晚期癌症患者中的前所未有的成功提供了原则性证据，即利用免疫系统，特别是 T 细胞，可以成为消除癌症的有效方法。这激发了人们强烈的兴趣，希望了解放疗（RT）的免疫调节作用，这一领域实际上早在一个多世纪前就已经进行了研究，但在几十年的时间里，这一领域基本被忽视了。随着 RT 产生的“新发现”的免疫原性反应，人们已经进行了许多尝试，将 RT 与 IOs 相结合，以增强抗肿瘤免疫力。然而，其潜在的机制尚未明确，这是一个需要大量研究的课题。因此，我们对 RT 诱导的免疫调节和 IOs 的分子基础进行了系统的文献检索，确定 IFN-JAK-STAT 途径是主要的调节途径。我们对相关研究的进一步分析表明，该途径对 RT 和 IOs 的反应的信号强度和持续时间可能决定最终的免疫结果。我们提出，靶向该轴可以增强 RT 的免疫刺激作用和 IOs 的放射增敏作用，从而促进 RT 和 IOs 联合治疗的疗效。
