Accumulating evidence suggests the potential for radiation therapy to generate antitumor immune responses against tumor cells by inducing immunogenic cell death and phenotypic changes. We recently found that ionizing radiation upregulated karyopherin α2 (KPNA2) in HT-29 colorectal tumor cells using quantitative proteomic analysis. To determine whether this increased KPNA2 could function as a damage-associated molecular pattern to induce antitumor immune responses, mouse bone-marrow-derived dendritic cells (BMDCs) were treated with KPNA2. KPNA2 enhanced the surface expression of CD40, CD54, CD80, CD86, and MHC class I/II on BMDCs. DCs treated with KPNA2 exhibited increased secretion of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-23, and TNF-α. Co-culture of CD4(+) T cells and KPNA2-treated DCs resulted in induction of Th1/17 cytokines (IFN-γ and IL-17) and reduction of TGF-β production. Moreover, KPNA2-treated DCs were capable of increasing granzyme B and perforin expression in cytotoxic T lymphocytes. These results demonstrated that radiation-induced dying colorectal cancer cells released considerable amounts of KPNA2 that induce the maturation and activation of DCs for synergistic antitumor effect of radiation.

中文翻译：

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在体外通过辐射上调的核转运蛋白α2诱导免疫原性细胞死亡。

越来越多的证据表明，放射疗法可能通过诱导免疫原性细胞死亡和表型改变而产生针对肿瘤细胞的抗肿瘤免疫应答。我们最近发现，使用定量蛋白质组学分析，电离辐射上调了HT-29大肠肿瘤细胞中的核球蛋白α2（KPNA2）。为了确定这种增加的KPNA2是否可以作为与损伤相关的分子模式来诱导抗肿瘤免疫反应，用KPNA2处理了小鼠骨髓来源的树突状细胞（BMDC）。KPNA2增强了BMDC上CD40，CD54，CD80，CD86和MHC I / II类的表面表达。用KPNA2处理的DC表现出促炎性细胞因子（例如IL-1β，IL-6，IL-12，IL-23和TNF-α）分泌增加。CD4（+）T细胞和KPNA2处理的DC的共培养导致Th1 / 17细胞因子（IFN-γ和IL-17）的诱导和TGF-β产生的减少。此外，KPNA2处理的DC能够增加细胞毒性T淋巴细胞中的颗粒酶B和穿孔素的表达。这些结果表明，辐射诱导的垂死结直肠癌细胞释放了大量的KPNA2，这些KPNA2诱导DC的成熟和激活，从而发挥辐射的协同抗肿瘤作用。