Department of Radiation Oncology, Center for Clinical Sciences Research (CCSR), Stanford University School of Medicine, 269 Campus Dr., Room 1260, Stanford, CA, 94305, USA.
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Cancer Immunol Immunother. 2022 Apr;71(4):839-850. doi: 10.1007/s00262-021-03036-w. Epub 2021 Aug 25.
The expression of immune-related genes in cancer cells can alter the anti-tumor immune response and thereby impact patient outcomes. Radiotherapy has been shown to modulate immune-related genes dependent on the fractionation regimen. To identify long-term changes in gene expression after irradiation, PC3 (p53 deleted) and LNCaP (p53 wildtype) prostate cancer cells were irradiated with either a single dose (SD, 10 Gy) or a fractionated regimen (MF) of 10 fractions (1 Gy per fraction). Whole human genome arrays were used to determine gene expression at 24 h and 2 months after irradiation. Immune pathway activation was analyzed with Ingenuity Pathway Analysis software. Additionally, 3D colony formation assays and T-cell cytotoxicity assays were performed. LNCaP had a higher basal expression of immunogenic genes and was more efficiently killed by cytotoxic T-cells compared to PC3. In both cell lines, MF irradiation resulted in an increase in multiple immune-related genes immediately after irradiation, while at 2 months, SD irradiation had a more pronounced effect on radiation-induced gene expression. Both immunogenic and immunosuppressive genes were upregulated in the long term in PC3 cells by a 10 Gy SD irradiation but not in LNCaP. T-cell-mediated cytotoxicity was significantly increased in 10 Gy SD PC3 cells compared to the unirradiated control and could be further enhanced by treatment with immune checkpoint inhibitors. Irradiation impacts the expression of immune-related genes in cancer cells in a fractionation-dependent manner. Understanding and targeting these changes may be a promising strategy for primary prostate cancer and recurrent tumors.
癌细胞中免疫相关基因的表达可以改变抗肿瘤免疫反应，从而影响患者的预后。放射治疗已被证明可以调节与分割方案相关的免疫相关基因。为了确定照射后基因表达的长期变化，用单次剂量（SD，10Gy）或 10 个分数（每个分数 1Gy）的分割方案（MF）照射 PC3（p53 缺失）和 LNCaP（p53 野生型）前列腺癌细胞。使用全人类基因组芯片在照射后 24 小时和 2 个月时确定基因表达。用 Ingenuity Pathway Analysis 软件分析免疫途径的激活。此外，还进行了 3D 集落形成测定和 T 细胞细胞毒性测定。与 PC3 相比，LNCaP 具有更高的免疫原性基因基础表达，并且更容易被细胞毒性 T 细胞杀死。在两种细胞系中，MF 照射后立即导致多种免疫相关基因的增加，而在 2 个月时，SD 照射对辐射诱导的基因表达有更明显的影响。在 PC3 细胞中，10Gy SD 照射会导致长期的免疫原性和免疫抑制性基因上调，但在 LNCaP 中则不会。与未照射对照相比，10Gy SD PC3 细胞中的 T 细胞介导的细胞毒性显著增加，并且可以通过免疫检查点抑制剂的治疗进一步增强。照射以与分割相关的方式影响癌细胞中免疫相关基因的表达。了解和靶向这些变化可能是治疗原发性前列腺癌和复发性肿瘤的一种有前途的策略。
