Chronic kidney disease facilitates TNF-α + neutrophils dysfunction and progression in oral squamous cell carcinoma.

BACKGROUND AND AIMS

The risk of cancer in patients with chronic kidney disease (CKD), particularly in those on dialysis is high. However, the underlying mechanism remains unclear. Moreover, the involvement of CKD in the progression of oral squamous cell carcinoma (OSCC) is still not fully understood. In this study, we aimed to investigate the role and mechanism of CKD in OSCC.

METHODS

The correlation between peripheral blood cell analysis and clinical characteristics was tested in patients with OSCC with CKD or non-CKD. Immune cell infiltration in the tumor microenvironment of OSCC was assessed using multicolor immunofluorescences. In addition, a mouse model of OSCC under CKD conditions was established and the effect of CKD on tumor growth was examined. Single-cell RNA sequencing (scRNA-seq) was performed using fresh tumor samples obtained from the mouse model. The interactions between OSCC cells and neutrophils were evaluated in vitro.

RESULTS

A cohort of 52 patients with OSCC was included in the study, among whom 23 had CKD. Patients in the CKD group showed a significant decrease of lymphocyte counts in peripheral blood compared with those in the non-CKD group. Furthermore, patients with CKD exhibited more aggressive lymph node metastasis than did those in the non-CKD group. The subcutaneous tumor mouse model under CKD conditions showed greater proliferative capacity than did the non-CKD group. The scRNA-seq results indicated that the percentages of neutrophils and T lymphocytes were decreased in the tumor tissues of CKD mice compare to non-CKD mice. A total of five neutrophil subpopulations were identified in the tumor microenvironment, including Hexb+, tumor necrosis factor-α + (TNF-α+), Retnig+, Cxcl10, and CD74 neutrophils. Among these, the proportion of TNF-α + neutrophils significantly decreased, which inhibited proliferation and promoted apoptosis via releasing TNF-α + in OSCC cell lines. In addition, a total of ten lymphocyte subpopulations were identified, among them the percentages of regulatory T cells (Tregs) and cytotoxic T lymphocytes (CTLs) changed significantly. Additionally, TNF-α + neutrophils regulated them in tumor microenvironment via chemokines.

CONCLUSION

Our findings indicate that immune cell dysfunction is a significant characteristic of patients with OSCC and CKD, and that TNF-α + neutrophils facilitate the progression of OSCC via releasing TNF-α + and orchestrating the functional dynamics of Tregs and CTLs. Collectively, these results offer a novel insight into the "kidney-oral" axis as a promising target for OSCC.