Abstract
Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal carcinoma (EC) in China. Although the PD-1 inhibitor pembrolizumab has been approved to treat patients with EC, its therapeutic efficacy is limited. Thus, additional immunotherapeutic targets for EC treatment are needed. Programmed Death-1 Homolog (PD-1H) is a negative checkpoint regulator that inhibits antitumor immune responses. Here, PD-1H expression in 114 patients with ESCC was evaluated by immunohistochemistry. Next, 12 randomly selected tumor tissue sections were used to assess the colocalization of PD-1H protein and multiple immune markers by multiplex immunohistochemistry. Our results demonstrated that PD-1H was expressed at high frequency in ESCC tumor tissues (85.1%). PD-1H protein was predominantly expressed in CD68+ tumor-associated macrophages and expressed at low levels in CD4+ T cells and CD8+ T cells in ESCC tumor tissues. Furthermore, based on ESCC data in The Cancer Genome Atlas (TCGA), the gene expression levels of PD-1H were positively associated with the infiltration levels of immune-activated cells especially CD8+ cytotoxic T cells. In contrast, the gene expression levels of PD-1H were negatively correlated with myeloid-derived suppressor cells (MDSCs). Importantly, PD-1H expression in tumor sites was significantly correlated with favorable overall survival in patients with ESCC. Collectively, our findings first provided direct information on the PD-1H expression pattern and distribution in ESCC, and positive correlation of PD-1H expression with overall survival suggested PD-1H expression levels could be a significant prognostic indicator for patients with ESCC. Future studies need to explore the immunoregulatory of PD-1H in the tumor microenvironment of ESCC.
Highlights
Esophageal carcinoma (EC) is one of the most fatal diseases worldwide and is the fourth most common cause of cancerrelated death in China (Chen et al, 2016; Feng et al, 2019)
Following the initial identification of the immune checkpoint receptors CTLA-4 and programmed death-1 (PD-1), other Ig superfamily T-cell inhibitory ligands/receptors, such as LAG-3, TIM-3, TIGIT, BTLA, B7-H3, and B7-H4 have been indicated as important regulators of antitumor immunity
Unlike other immune checkpoint receptors that are induced on activated T lymphocytes, Programmed Death-1 Homolog (PD-1H) was reported to be constitutively expressed on myeloid cells and naïve T cells, exerting both ligand and receptor functions (Lines et al, 2014a; Gao et al, 2017; ElTanbouly et al, 2020)
Summary
Esophageal carcinoma (EC) is one of the most fatal diseases worldwide and is the fourth most common cause of cancerrelated death in China (Chen et al, 2016; Feng et al, 2019). Targeting immune checkpoints has been demonstrated as a promising strategy in EC. Programmed Death-1 Homolog (PD-1H), known as V-domain Immunoglobulin Suppressor of T-cell activation (VISTA), DD1α, c10orf, Dies, or Gi24, is a novel T-cell cosignaling molecule. Previous studies demonstrated that the immuneregulatory pathways for PD-1 and PD-1H are functionally nonredundant by using PD-1H and programmed death-1 (PD-1) knockout mice (Liu et al, 2015). PD-1H can function as both a receptor in T lymphocytes and a ligand on antigen-presenting cells (Bharaj et al, 2014; Flies et al, 2014; Le Mercier et al, 2014; Lines et al, 2014a). Considering different expression patterns of PD-1H and its nonredundant activities compared to other immune checkpoint regulators, PD-1H has become a promising target of cancer immunotherapy [11]
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