The presence of tumour‐infiltrating neutrophils is an independent adverse prognostic feature in clear cell renal cell carcinoma

Abstract

Tumour-promoting inflammation is an emerging hallmark of cancer that is increasingly recognised as a therapeutic target. As a constituent measure of inflammation, tumour-infiltrating neutrophils (TINs) have been associated with inferior prognosis in several cancers. We analysed clinically annotated cohorts of clear cell renal cell carcinoma (ccRCC) to assess the presence of neutrophils within the tumour microenvironment as a function of outcome. We centrally reviewed ccRCC surgical resection and fine-needle aspiration (FNA) specimens, including primary and metastatic sites, from three centres. TINs were scored based on the presence of neutrophils in resection and FNA specimens by two pathologists. TIN count was correlated with tumour characteristics including stage, WHO/ISUP grade, and immunohistochemistry (IHC). In parallel, we performed CIBERSORT analysis of the tumour microenvironment in a cohort of 516 ccRCCs from The Cancer Genome Atlas (TCGA). We included 102 ccRCC cases comprising 65 resection specimens (37 primary and 28 metastatic resection specimens) and 37 FNAs from primary lesions. High TINs were significantly associated with worse overall survival (p = 0.009) independent of tumour grade and stage. In ccRCCs sampled via FNA, all cases with high TINs had distant metastasis, whereas they were seen in only 19% of cases with low TINs (p = 0.0003). IHC analysis showed loss of E-cadherin in viable tumour cells in areas with high TINs, and neutrophil activation was associated with elastase and citrullinated histone H3 expression (cit-H3). In the TCGA cohort, neutrophilic markers were also associated with worse survival (p < 0.0001). TINs are an independent predictor of worse prognosis in ccRCC, which have the potential to be assessed at the time of first biopsy or FNA. Neutrophils act directly on tumour tissue by releasing elastase, a factor that contributes to the breakdown of cellcell adhesion and to facilitate tumour dissemination.

A Predictive Model Based on Pyroptosis-Related Gene Features Can Effectively Predict Clear Cell Renal Cell Carcinoma Prognosis and May Be an Underlying Target for Immunotherapy

“…For example, Braun et al found a higher proportion Disease Markers of exhausted CD8 + T cells and immunosuppressive M2-like macrophages in patients with advanced ccRCC, and this inhibitory effect showed progressive immune dysfunction as the disease stage of ccRCC progressed [36]. Tessier-Cloutier et al found that ccRCC microenvironment is infiltrated with a large number of neutrophils, many of which act directly on tumor tissue by releasing elastase thereby promoting tumor spread [37]. The consequences indicate therapy against microenvironmental immunity cellulas can be an efficient strategy for delaying disease progression and activating immune responses.…”

Bioinformatics analysis of immune-related prognostic genes and immunotherapy in renal clear cell carcinoma

“…Castle et al [21] reported that dendritic cells activate T cells in patients and increase cytotoxic T cell production, exerting anti-tumor effects. Basile et al [22] demonstrated that high tumor-infiltrating neutrophils were linked to poor overall survival in ccRCC patients. A previous study found that in patients with ccRCC mast cells [23] and high infiltration, the immune treatment may be effective with an improved prognosis.…”

Identification of a Prognostic Model Based on Immune Cell Signatures in Clear Cell Renal Cell Carcinoma

“…Myeloid dendritic cells generated chemokine ligand 17 that recruited T cells as well as other activated antigen-presenting cells and was an independent prognostic factor for OS in ccRCC patients [ 25 ]. Tumor-infiltrating neutrophils were involved in the prognostic deterioration of ccRCC by releasing elastase that broke down cell-cell adhesion and promoted tumor propagation [ 26 ]. Interferon receptors, cytokine receptors and interleukins could impair the prognosis of ccRCC through reconfiguring the immune landscape of TME [ 27 , 28 ].…”