Abstract
Tumor growth and survival requires a particularly effective immunosuppressant tumor microenvironment (TME) to escape destruction by the immune system. While immunosuppressive checkpoint markers like programmed cell death 1 ligand (PD-L1) are already being targeted in clinical practice, lymphocyte-activation-protein 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and V-domain Ig suppressor of T cell activation (VISTA) inhibitors are currently under investigation in clinical trials. Reliable findings on the expression status of those immune checkpoint inhibitors on tumor-infiltrating lymphocytes (TILs) in the TME of oropharyngeal squamous cell carcinoma (OPSCC) are lacking. This work aims to describe the expression of LAG-3, TIM-3, and VISTA expression in the TME of OPSCC. We created a tissue microarray of paraffin-embedded tumor tissue of 241 OPSCC. Expression of the immune checkpoint protein LAG-3, TIM-3, and VISTA in OPSCC was evaluated using immunohistochemistry and results were correlated with CD8+ T-cell inflammation and human papillomavirus (HPV)-status. 73 OPSCC stained positive for LAG-3 (31%; HPV+:44%; HPV-:26%, p = 0.006), 122 OPSCC stained positive for TIM-3 (51%; HPV+:70%; HPV-:44%, p < 0.001) and 168 OPSCC (70%; HPV+:75%; HPV-:68%, p = 0.313) for VISTA. CD8+ T-cells were significantly associated with LAG-3, TIM-3 and VISTA expression (p < 0.001, p < 0.001, p = 0.007). Immune checkpoint therapy targeting LAG-3, TIM-3, and/or VISTA could be a promising treatment strategy especially in HPV-related OPSCC. Future clinical trials investigating the efficacy of a checkpoint blockade in consideration of LAG-3, TIM-3, and VISTA expression are required.
Highlights
Immune checkpoints (ICP) are expressed in healthy tissue to prevent autoimmune disease and are often being altered by cancer cells to evade the host immune system [1].Bypassing immune surveillance and immune response of tumor cells is controlled by the upregulation of co-inhibitory checkpoints and the delivery of inhibitory signals toT-cells
Patients with an human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) were less frequently smokers and drinkers and tumors were predominantly located in the tonsil region (p = 0.012) and associated with lymph node metastasis (p = 0.001)
Little is known about the importance of the expression status of additional ICP in the tumor microenvironment (TME) of OPSCC, and especially according to HPV-status
Summary
Immune checkpoints (ICP) are expressed in healthy tissue to prevent autoimmune disease and are often being altered by cancer cells to evade the host immune system [1].Bypassing immune surveillance and immune response of tumor cells is controlled by the upregulation of co-inhibitory checkpoints and the delivery of inhibitory signals toT-cells. Immune checkpoints (ICP) are expressed in healthy tissue to prevent autoimmune disease and are often being altered by cancer cells to evade the host immune system [1]. Bypassing immune surveillance and immune response of tumor cells is controlled by the upregulation of co-inhibitory checkpoints and the delivery of inhibitory signals to. Tumors activate certain ICP, against tumor-antigen specific T-cells, as a mechanism of immune resistance [2]. Lymphocyte-activation gene 3 (LAG-3) belongs to the immunoglobulin superfamily (IgSF) and is displayed on activated immune cells e.g., several forms of T-lymphocytes (CD4+, CD8+, regulatory T-cells (Treg) [9,10]. LAG-3 binds with higher affinity than CD4 to major histocompatibility complex II (MHC II). This is supported by its gene sequence, which is 20%
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