Immune‐checkpoint molecules on regulatory T‐cells as a potential therapeutic target in head and neck squamous cell cancers

Abstract

Immune‐checkpoint inhibitors improve the survival of head and neck squamous cell carcinoma (HNSCC) patients. Although recent studies have demonstrated that the tumor immune microenvironment (TIME) has critical roles in immunotherapy, the precise mechanisms involved are unclear. Therefore, further investigations of TIME are required for the improvement of immunotherapy. The frequency of effector regulatory T‐cells (eTregs) and the expression of immune‐checkpoint molecules (ICM) on eTregs and conventional T‐cells (Tconvs) both in peripheral blood lymphocytes (PBL) and tumor‐infiltrating lymphocytes (TIL) from HNSCC patients were analyzed by flow cytometry and their distributions were evaluated by multi‐color immunofluorescence microscopy. High frequency eTreg infiltration into HNSCC tissues was observed and high expressions of CD25, FOXP3, stimulatory‐ICM (4‐1BB, ICOS, OX40 and GITR) and inhibitory‐ICM (programmed cell death‐1 [PD‐1] and cytotoxic T‐lymphocyte‐associated protein‐4 [CTLA‐4]) were found on invasive eTregs. In contrast, the expression of stimulatory‐ICM on Tconvs was low and the expression of inhibitory‐ICM was high. In addition, ICM‐ligands (programmed cell death‐1 [PD‐L1], galectin‐9 and CEACAM‐1) were frequently expressed on cancer cells. PD‐L1 and galectin‐9 were also expressed on macrophages. PD‐1+ T‐cells interacted with PD‐L1+ cancer cells or PD‐L1+ macrophages. This suggested that in TIL, eTregs are highly activated, but Tconvs are exhausted or inactivated by eTregs and immune‐checkpoint systems, and ICM and eTregs are strongly involved in the creation of an immunosuppressive environment in HNSCC tissues. These suggested eTreg targeting drugs are expected to be a combination partner with immune‐checkpoint inhibitors that will improve immunotherapy of HNSCC.

ICOS+ Tregs: A Functional Subset of Tregs in Immune Diseases

“…ICOS + Tregs, which were suggested to have a potent suppressive ability compared with their ICOS – counterpart, therefore, play a dominant role in the process of immune escape. Recently, with a growing numbers of studies focusing on the immunophenotype of TILs, an increased percentage of ICOS + Tregs have been observed in more and more types of tumor tissues, including melanoma, ( 134 ) head and neck squamous cell cancers, ( 135 ) gastric cancers, ( 136 ) breast cancer, ( 137 ) ovarian cancer, ( 138 ) clear cell renal cell carcinoma, ( 139 ) and acute myeloid leukemia (AML) ( 140 ). Furthermore, the elevated proportion of ICOS + Tregs was shown to be associated with a bad outcome in most cases, and it was indicated as a better predictor of prognosis than the percentage of total Tregs under some circumstances.…”

Immuno-Oncological Biomarkers for Squamous Cell Cancer of the Head and Neck: Current State of the Art and Future Perspectives

“…Immune checkpoints (f.i. PD-1) expressed on T cells have low sensitivity using immunohistochemical detection on tumoral tissue, hence the recommendation of combining both techniques in the future for adequately assessing the PD-L1 status of SCCHN [ 54 , 177 ]. In summary, aforementioned data about circulating blood cells and their expressed surface proteins seem worthwhile for contemporary evaluation, providing further insight in tumor biology and the immunological profile of SCCHN.…”

Prognostic Biomarker KIF18A and Its Correlations With Immune Infiltrates and Mitosis in Glioma

“…Additionally, studies have shown that the tumour-suppressive immune microenvironment is also an important factor for poor prognosis in glioma patients ( Suzuki et al, 2020 ). To deeply explore the potential biological functions of KIF18A and further explain why high expression of KIF18A is associated with poor prognosis of patients, we conducted immune infiltration analysis based on the ssGSEA algorithm; the results indicated that the expression level of KIF18A was prominently correlated with Th2 cells and tumour-associated macrophages (TAMs), and the numbers of these two kinds of cells in the patient group with high expression of KIF18A were both highly expressed with significant statistical differences.…”