Immunological and Genetic Characterization of Patients With Head and Neck Cancer who Developed Recurrence
Immunological and Genetic Characterization of Patients With Head and Neck Cancer who Developed Recurrence
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DOI：
10.21873/anticanres.15942
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发表时间：
2022-08
影响因子：
2
通讯作者：
K. Yasui;Ryota Kondou;H. Miyata;A. Iizuka;T. Ashizawa;T. Nagashima;K. Ohshima;K. Urakami;Koji Muramatsu;T. Sugino;K. Yamaguchi;H. Ogawa;T. Onoe;H. Harada;H. Asakura;S. Murayama;T. Nishimura;Seiya Goto;S. Okada;Takashi Mukaigawa;S. Hamauchi;T. Yokota;Y. Onozawa;Y. Akiyama
中科院分区：
文献类型：
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作者：
K. Yasui;Ryota Kondou;H. Miyata;A. Iizuka;T. Ashizawa;T. Nagashima;K. Ohshima;K. Urakami;Koji Muramatsu;T. Sugino;K. Yamaguchi;H. Ogawa;T. Onoe;H. Harada;H. Asakura;S. Murayama;T. Nishimura;Seiya Goto;S. Okada;Takashi Mukaigawa;S. Hamauchi;T. Yokota;Y. Onozawa;Y. Akiyama
背景/目的：头颈部鳞状细胞癌（HNSCC）的复发率居高不下，因此控制复发是一个临床难题。为了阐明确切的机制，研究了负责复发的特异性免疫学生物标志物。患者和方法：使用火山图分析比较复发的HNSCC患者（n=8）和未复发的HNSCC患者（n=19）之间免疫应答相关和静冈癌症中心820癌症相关基因的表达水平以及来自全外显子组测序的基因突变。细胞因子和上皮-间质转化标志物基因进行了分析，使用定量PCR。肿瘤浸润淋巴细胞，免疫检查点分子，和人乳头瘤病毒状态进行了研究，使用免疫组化（IHC）。结果：27例可评估的HNSCCs患者在手术后接受了放射治疗。8例患者复发。复发患者的TP 53突变倾向于高于未复发患者（75%对31.6%）。基因表达谱显示T细胞活化基因（ICOS、CD 69和CD 83）下调，ERBB 4、EGFR、VEGF、HIF 1A、TGFB 1、TWIST 1、IL-8和PAX 7基因上调，提示TP 53突变-TGF-β1-PAX 7通路和上皮-间质转化激活。此外，IHC显示复发肿瘤中T细胞积聚减少和M2型巨噬细胞浸润增加的趋势。结论：肿瘤微环境中TP 53突变介导的免疫抑制状态和TGF-β1-PAX 7介导的EMT可能有助于促进HNSCC患者术后放疗后的复发。
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. Patients and Methods: 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). Results: 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. Conclusion: 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.