Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Oral Oncol. 2021 Dec;123:105587. doi: 10.1016/j.oraloncology.2021.105587. Epub 2021 Oct 27.
IRX-2 is a homologous cell-derived multi-cytokine biologic with multifaceted immune modulatory effects that has been shown to induce increased lymphocyte infiltration into primary tumors in oral cavity carcinoma. Our objective was to characterize tumor immune gene expression and epigenomic changes after neoadjuvant IRX-2 immunotherapy in patients with squamous cell carcinoma of the oral cavity.
A randomized phase II trial was conducted of the IRX regimen 3 weeks prior to surgery for previously untreated patients with Stage II-IV oral cavity carcinoma. The treatment regimen consisted of low dose (300 mg/m) cyclophosphamide (day 1) followed by 10 days of regional perilymphatic IRX-2 cytokine injections and daily oral indomethacin, zinc and omeprazole (Regimen 1) compared to the identical regimen without the IRX-2 cytokines (Regimen 2). The NanoString immune panel (730 genes) and Infinium MethylationEPIC BeadChip were performed to assess the gene expression and DNA methylation signatures, respectively, in pre- and post-immunotherapy tumor samples.
A total of 51 and 79 immune-related genes were found upregulated and downregulated, respectively, in the samples from Regimen 1 patients after treatment, while 51 and 56 were found upregulated and downregulated in the samples for Regimen 2. When comparing the changes between the two regimens, we identified 9 genes significantly different, including DMBT1, a potential tumor suppressor, functioning in tumor invasion of head and neck cancer. The exploration of DNA methylation showed slight overall hypermethylation after treatment in both regimens, especially for Regimen 1 immune responders, and methylation-based cell type deconvolution demonstrated high concordance with tumor infiltrating T lymphocyte cell counts.
While a consistent patient response after treatment was observed, most changes were similar between regimens, indicating a subtle, targeted, or patient-specific effect of IRX-2 cytokines. Change in DMBT1 expression was a unique finding that will require further study to better understand its significance.
IRX-2 是一种同源细胞衍生的多细胞因子生物制剂，具有多方面的免疫调节作用，已被证明可诱导口腔癌原发性肿瘤中淋巴细胞浸润增加。我们的目的是描述新辅助 IRX-2 免疫治疗后口腔鳞状细胞癌患者的肿瘤免疫基因表达和表观基因组变化。
对 II-IV 期口腔癌未接受治疗的患者进行了 IRX 方案的随机 II 期试验，该方案在手术前 3 周进行。治疗方案包括低剂量（300mg/m）环磷酰胺（第 1 天），随后进行 10 天的局部周围淋巴液 IRX-2 细胞因子注射和每日口服吲哚美辛、锌和奥美拉唑（方案 1），与不含 IRX-2 细胞因子的相同方案（方案 2）进行比较。进行了 NanoString 免疫小组（730 个基因）和 Infinium MethylationEPIC BeadChip 以分别评估治疗前后肿瘤样本中的基因表达和 DNA 甲基化特征。
方案 1 患者治疗后样本中分别有 51 个和 79 个免疫相关基因上调和下调，方案 2 患者样本中分别有 51 个和 56 个免疫相关基因上调和下调。比较两种方案之间的变化，我们发现有 9 个基因明显不同，包括 DMBT1，这是一种潜在的肿瘤抑制因子，在头颈部癌症的肿瘤侵袭中起作用。DNA 甲基化的探索表明，两种方案治疗后均出现轻微的总体过度甲基化，特别是在方案 1 的免疫应答者中，基于甲基化的细胞类型去卷积与肿瘤浸润 T 淋巴细胞计数具有高度一致性。
尽管观察到治疗后患者的一致反应，但大多数变化在方案之间相似，表明 IRX-2 细胞因子具有微妙、靶向或特定于患者的作用。DMBT1 表达的变化是一个独特的发现，需要进一步研究以更好地了解其意义。
