Abstract
Endogenous control mechanisms, including immune checkpoints and immunosuppressive cells, are exploited in the process of tumorigenesis to weaken the anti-tumor immune response. Cancer treatment by chemotherapy or immune checkpoint inhibition can lead to changes of checkpoint expression, which influences therapy success. Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) were isolated from head and neck squamous cell carcinoma (HNSCC) patients (n = 23) and compared to healthy donors (n = 23). Immune checkpoint expression (programmed cell death ligand 1 (PD-1), tumor necrosis factor receptor (TNFR)-related (GITR), CD137, tumor necrosis factor receptor superfamily member 4 (TNFRSF4) (OX40), t-cell immunoglobulin and mucin-domain containing-3 (TIM3), B- and T-lymphocyte attenuator (BTLA), lymphocyte-activation gene 3 (LAG3)) was determined on immune cells by flow cytometry. PD-L1 expression was detected on tumor tissue by immunohistochemistry. Immune cells were treated with immuno- and chemotherapeutics to investigate treatment-specific change in immune checkpoint expression, in vitro. Specific changes of immune checkpoint expression were identified on PBL and TIL of HNSCC patients compared to healthy donors. Various chemotherapeutics acted differently on the expression of immune checkpoints. Changes of checkpoint expression were significantly less pronounced on regulatory T cells compared to other lymphocyte populations. Nivolumab treatment significantly reduced the receptor PD-1 on all analyzed T cell populations, in vitro. The specific immune checkpoint expression patterns in HNSCC patients and the investigated effects of immunomodulatory agents may improve the development and efficacy of targeted immunotherapy.
Highlights
The results of the KEYNOTE-048 clinical trial led to the proposed use of the PD-1 inhibitor pembrolizumab plus platinum and 5-fluorouracil (5-FU) as an appropriate first-line treatment for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) and pembrolizumab monotherapy as a first-line treatment for PD-L1-positive recurrent or metastatic HNSCC [16]. These findings suggest that immunotherapy in combination with chemotherapy or as monotherapy is able to achieve an improvement in overall survival of HNSCC patients, but not as superior as initially supposed
The present study focuses on the co-inhibitory checkpoints PD-1, t-cell immunoglobulin and mucin-domain containing-3 (TIM3), B- and T-lymphocyte attenuator (BTLA) and lymphocyte-activation gene 3 (LAG3), and the co-stimulatory checkpoints glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related (GITR), CD137, and tumor necrosis factor receptor superfamily member 4 (OX40, TNFRSF4)
Peripheral blood samples were obtained from 23 healthy donors and 23 HNSCC patients, who were treated in the local ENT-department (Table 1)
Summary
Immune evasion is one of the major mechanisms for uncontrolled proliferation and migration of tumor cells [1]. One of the recently most discussed immune evasion mechanisms is the establishment of an immunosuppressive microenvironment by the tumor [2]. This includes the recruitment of immunosuppressive cells like regulatory T cells (Treg) to the tumor site, as well as the enrichment of these cells in the peripheral blood of tumor patients [3]. Immune checkpoints appear to play an important role in the tumor microenvironment and can be manipulated as a mechanism of tumor immune evasion [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
