Immunological and Genetic Characterization of Patients With Head and Neck Cancer who Developed Recurrence

• Published in: Anticancer research 2022-09, Vol.42 (9), p.4417-4428
• Main Authors: Yasui, Kazuaki, Kondou, Ryota, Miyata, Haruo, Iizuka, Akira, Ashizawa, Tadashi, Nagashima, Takeshi, Ohshima, Keiichi, Urakami, Kenichi, Muramatsu, Koji, Sugino, Takashi, Yamaguchi, Ken, Ogawa, Hirofumi, Onoe, Tsuyoshi, Harada, Hideyuki, Asakura, Hirofumi, Murayama, Shigeyuki, Nishimura, Tetsuo, Goto, Seiya, Okada, Shinichi, Mukaigawa, Takashi, Hamauchi, Satoshi, Yokota, Tomoya, Onozawa, Yusuke, Akiyama, Yasuto
• Format: Article
• Language: English
• Subjects: Biomarkers; Cancer; CD69 antigen; CD83 antigen; Cell activation; Cytokines; ErbB-2 protein; Gene expression; Genes; Head & neck cancer; Head and neck carcinoma; Human papillomavirus; Immune checkpoint; Immune response; Immune system; Immunohistochemistry; Immunology; Interleukin 8; Lymphocytes; Lymphocytes T; Macrophages; Mesenchyme; Metastases; Mutation; p53 Protein; Patients; Radiation; Radiation therapy; Squamous cell carcinoma; Transcription activation; Transforming growth factor-b1; Tumor microenvironment; Tumor-infiltrating lymphocytes; Tumors; Vascular endothelial growth factor; Viruses
• ISSN: 0250-7005; 1791-7530
• 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. 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.