PD-1/PD-L1 Axis, Rather Than High-Mobility Group Alarmins or CD8+ Tumor-Infiltrating Lymphocytes, Is Associated With Survival in Head and Neck Squamous Cell Carcinoma Patients Who Received Surgical Resection

Abstract

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, P < 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, P < 0.01; 105.10 ± 108.25, P < 0.05; 13.00(6.75, 32.25), P < 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.

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

“…Our results also indicate that CD8 T cells and memory activated CD4 T cells were highly expressed in low immune risk groups, while memory resting CD4 T cells were downregulated. Furthermore, a favorable, prognostic role of CD8 T cell infiltration was associated with better OS in HNSCC patients [14,15,35]. Together, Fig.…”

Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

“…The studies that did not fulfill all the inclusion criteria were discarded. Of these, seven were excluded because they did not report the outcome of LSCC separately from other locations of HNSCC [12,[15][16][17][18][19][20], eight because no HRs were available [21][22][23][24][25][26][27][28][29], one study because they reported outcome in terms of local control [30], one study that evaluated Il-12R expression on tumor cells [31], and one study that evaluated lymphocytes in peripheral blood [32]. This left 11 studies for the analysis (Fig- Studies were selected if they met the following inclusion criteria: (1) prognostic value of TIL was evaluated in patients with LSCC (primary or recurrent), (2) TIL were evaluated either immunohistochemically (CD8+, CD4+, and/or CD3+) and/or in hematoxylin-and eosin (HE)-stained sections, in resected specimens or in diagnostic biopsies, (3) TIL were evaluated either in tumor epithelium and/or tumor stroma, (4) prognostic value of TIL was evaluated by time-to-event survival analysis with overall survival (OS) and/or disease-free survival (DFS), and (5) original articles published in English.…”

Biological Functions of HMGN Chromosomal Proteins

“…Moreover, low doses of HMGN1 with anti-CD4 depleting antibody promoted the expansion of anti-tumor CD8 T cells by rescuing them from exhaustion [91]. In a recent study on patients with head and neck carcinoma, it was observed that cytoplasmic localization and secretion of HMGN1 was associated with the recruitment of tumor infiltering lymphocytes [92]. A proteomics study in HMGN1 knockout revealed the role of HMGN1 in complement and coagulation cascade and interferon response in cancer cells, reinforcing the role of HMGN1 in regulating immune response [93].…”