Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Radiation and Proton Therapy Center, Shizuoka Cancer Center Hospital, Shizuoka, Japan.
Anticancer Res. 2022 Sep;42(9):4417-4428. doi: 10.21873/anticanres.15942.
BACKGROUND/AIM: The recurrence rate of head and neck squamous cell carcinoma (HNSCC) remains high; thus the control of recurrence is a clinical problem to be challenged. To clarify the precise mechanism, specific immunological biomarkers responsible for recurrence were investigated.
The expression levels of immune response-associated and Shizuoka Cancer Center 820 cancer-associated genes, and genetic mutations from whole-exome sequencing were compared between HNSCC patients who developed recurrence (n=8) and HNSCC patients who did not develop recurrence (n=19) using a volcano plot analysis. Cytokine and epithelial-mesenchymal transition marker genes were analyzed using quantitative PCR. Tumor-infiltrating lymphocytes, immune checkpoint molecules, and human papilloma virus status were investigated using immunohistochemistry (IHC).
Twenty-seven evaluable patients with HNSCCs received radiation therapy after surgery. Recurrence was identified in 8 patients. TP53 mutations tended to be higher in patients who developed recurrence than in those who did not develop recurrence (75% vs. 31.6%). Gene expression profiling showed the down-regulation of T cell activation genes (ICOS, CD69 and CD83) and the upregulation of the ERBB4, EGFR, VEGF, HIF1A, TGFB1, TWIST1, IL-8, and PAX7 genes, which suggested the activation of the TP53 mutation-TGF-β1-PAX7 pathway and epithelial-mesenchymal transition. Additionally, IHC indicated a tendency toward a reduction in T cell accumulation and an increase in M2-type macrophage infiltration in tumors that recurred.
A TP53 mutation-mediated immune-suppressive state in the tumor microenvironment and TGF-β1-PAX7-mediated EMT might contribute to the promotion of recurrence in patients with HNSCC after postoperative radiotherapy.
背景/目的：头颈部鳞状细胞癌（HNSCC）的复发率仍然很高；因此，控制复发是一个需要解决的临床问题。为了阐明确切的机制，研究了与复发相关的特定免疫生物标志物。
使用火山图分析比较了发生复发（n=8）和未发生复发（n=19）的 HNSCC 患者的免疫反应相关和静冈癌症中心 820 种癌症相关基因以及全外显子测序的遗传突变的表达水平。使用定量 PCR 分析细胞因子和上皮-间充质转化标记基因。使用免疫组化（IHC）研究肿瘤浸润淋巴细胞、免疫检查点分子和人乳头瘤病毒状态。
27 名接受手术治疗后接受放射治疗的 HNSCC 患者可进行评估。8 名患者发生了复发。与未发生复发的患者相比，发生复发的患者中 TP53 突变的倾向更高（75%比 31.6%）。基因表达谱显示 T 细胞激活基因（ICOS、CD69 和 CD83）下调，以及 ERBB4、EGFR、VEGF、HIF1A、TGFB1、TWIST1、IL-8 和 PAX7 基因上调，提示 TP53 突变-TGF-β1-PAX7 通路和上皮-间充质转化的激活。此外，IHC 表明，在复发肿瘤中 T 细胞积累减少，M2 型巨噬细胞浸润增加。
肿瘤微环境中 TP53 突变介导的免疫抑制状态和 TGF-β1-PAX7 介导的 EMT 可能有助于促进接受术后放疗的 HNSCC 患者的复发。
