Yang Fan, Zeng Ziqing, Li Jing, Zheng Yu, Wei Feng, Ren Xiubao
Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Front Oncol. 2018 Dec 11;8:604. doi: 10.3389/fonc.2018.00604. eCollection 2018.
In current studies, the influence of tumor immune microenvironment on tumorigenesis and tumor progression has been widely explored. In the present study, we investigated the expression and significance of high mobility group box 1 (HMGB1), HMG nucleosome-binding protein 1 (HMGN1), the receptor programmed cell death 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1) in head and neck squamous cell carcinoma (HNSCC). We explored whether HMGB1 and HMGN1 take part in recruiting T cells to HNSCC microenvironment. Furthermore, we assessed the prognostic value of HMG proteins, TILs, and PD-1/PD-L1 in postoperative patients. Tumor tissue sections were collected from 81 cases of patients with resectable HNSCC. All patients' information was integrated with clinical and pathological records, as well as follow-up data. We used immunohistochemistry to examine the subcellular localization and expression levels of HMGB1 and HMGN1, as well as tumor CD3+, CD8+, FOXP3+ lymphocyte infiltration, and the expression of immune inhibiting molecules PD-1/PD-L1. Results showed that there was no significant difference in the number of CD8+ and FOXP3+ T cells between the two groups with or without HMGB1 cytoplasmic expression in tumor tissues. The number of CD3+ T cells in HMGB1 cytoplasmic expression group (339.39 ± 230.76) was more than that in group without HMGB1 cytoplasmic expression (233.30 ± 230.91, < 0.05). The number of CD3+, CD8+, and FOXP3+ T cells in HMGN1 cytoplasmic expression group [400.74 ± 224.04, 158.10 ± 112.10, 36.00(15.00, 69.00)] was more than that in group without HMGN1-cytoplasmic expression [222.84 ± 217.78, < 0.01; 105.10 ± 108.25, < 0.05; 13.00(6.75, 32.25), < 0.01]. The positive rates of PD-1 and PD-L1 in tumor tissues were 29.6 and 67.9%, respectively. Multivariate analysis suggested that tumor expression of PD-L1 was an independent prognostic factor and PD-L1 overexpression indicated a poor overall survival (OS) and disease-free survival (DFS). Taken together, we concluded that HMGB1 and HMGN1 secreted by cancer cells may relate to recruitment of tumor infiltrating lymphocytes (TILs) in HNSCC. PD-1/PD-L1 axis, rather than HMG proteins or CD8+ tumor-infiltrating lymphocytes, has a critical role in tumor immune microenvironment and could predict the outcome of HNSCC patients who received surgical resection.
在当前研究中，肿瘤免疫微环境对肿瘤发生和肿瘤进展的影响已得到广泛探索。在本研究中，我们调查了高迁移率族蛋白B1（HMGB1）、HMG核小体结合蛋白1（HMGN1）、程序性细胞死亡蛋白1（PD - 1）及其配体程序性细胞死亡配体1（PD - L1）在头颈部鳞状细胞癌（HNSCC）中的表达及意义。我们探究了HMGB1和HMGN1是否参与将T细胞募集至HNSCC微环境。此外，我们评估了HMG蛋白、肿瘤浸润淋巴细胞（TILs）以及PD - 1/PD - L1在术后患者中的预后价值。收集了81例可切除HNSCC患者的肿瘤组织切片。所有患者的信息与临床和病理记录以及随访数据相结合。我们采用免疫组织化学法检测HMGB1和HMGN1的亚细胞定位及表达水平，以及肿瘤组织中CD3⁺、CD8⁺、FOXP3⁺淋巴细胞浸润情况和免疫抑制分子PD - 1/PD - L1的表达。结果显示，肿瘤组织中HMGB1细胞质表达阳性和阴性两组间CD8⁺和FOXP3⁺ T细胞数量无显著差异。HMGB1细胞质表达组的CD3⁺ T细胞数量（339.39 ± 230.76）多于无HMGB1细胞质表达组（233.30 ± 230.91，P < 0.05）。HMGN1细胞质表达组的CD3⁺、CD8⁺和FOXP3⁺ T细胞数量[400.74 ± 224.04，158.10 ± 112.10，36.00（15.00，69.00）]多于无HMGN1细胞质表达组[222.84 ± 217.78，P < 0.01；105.10 ± 108.25，P < 0.05；13.00（6.75，32.25），P < 0.01]。肿瘤组织中PD - 1和PD - L1的阳性率分别为29.6%和67.9%。多因素分析表明，肿瘤组织中PD - L1的表达是一个独立的预后因素，PD - L1过表达提示总生存期（OS）和无病生存期（DFS）较差。综上所述，我们得出结论，癌细胞分泌的HMGB1和HMGN1可能与HNSCC中肿瘤浸润淋巴细胞（TILs）的募集有关。PD - 1/PD - L1轴而非HMG蛋白或CD8⁺肿瘤浸润淋巴细胞在肿瘤免疫微环境中起关键作用，并且可以预测接受手术切除的HNSCC患者的预后。
