Prognostic Significance of NLR About NETosis and Lymphocytes Perturbations in Localized Renal Cell Carcinoma With Tumor Thrombus

Abstract

BackgroundNon-metastatic renal cell carcinoma (RCC) with tumor thrombus showed a greater tendency for developing metastases after surgery. Early identification of patients with high risk of poor prognosis is especially important to explore adjuvant treatment of improving outcomes. Neutrophil-to-lymphocyte ratio (NLR) was a systemic inflammation marker and outcome predictor in RCC, reflecting the chaos in systemic immune status in cancer as myeloid cell expansion and lymphatic cell suppression. Neutrophil extracellular traps (NET) formation (NETosis) is the process of neutrophils generating an extracellular DNA net-like structure. NETosis in tumor was demonstrated to conduce to the subsequent metastases of tumor. However, the role of NLR for systemic immune status and tumor local immune infiltration, especially for neutrophil-associated NETs, in non-metastatic RCC with thrombus remains unclear.Patients and MethodsIn our clinical cohort, we enrolled the clinical, pathologic, and preoperative laboratory parameters of 214 RCC patients with tumor thrombus who were treated surgically. The clinical endpoint was defined as cancer-specific survival (CSS). In our basic research cohort, RNA-seq, TCR-seq, and scRNA-seq data were analyzed. Patients who reached the endpoint as recurrence-free survival (RFS) were defined as the “High-risk” group. Otherwise, they were separated into the “Low-risk” group.ResultsIn the clinical cohort, NLR≥4 was an independent risk factor for 203 localized RCC with tumor thrombus. In the basic research cohort, tumor thrombi were separated into NETosis-thrombi belonging to the “High-risk” group and non-NETosis-thrombi to the “Low-risk” group. NETs induced by tumor-derived G-CSF in tumor thrombus has a mechanistic role in unfavorable prognosis. Besides, NETs-score from single sample GSEA (ssGSEA) algorithm was an independent prognostic factor validated in the TCGA data. Apart from the neutrophils-associated NETosis, systemic immune perturbations of lymphocytes occurred in the “High-risk” group, represented with decreased TCR diversity and increasingly high proportion of CD4-positive effector memory T (Tem) cells, which indirectly represented the state of lymphopenia.ConclusionsOur findings firstly demonstrated that neutrophils-associated NETosis and systemic lymphocytes perturbations were considered as tumor progression in patients of localized RCC with tumor thrombus, which reflected NLR≥4 as an independent risk factor for patients.

Critical Evaluation of a microRNA-Based Risk Classifier Predicting Cancer-Specific Survival in Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava

“…In line with nomograms and prediction models in metastasized RCC [ 27 , 28 ], researchers have also investigated the prognostic role of blood counts in RCC cases with tumor thrombus. Specifically, serum gamma-glutamyltransferase (GGT) [ 29 ], as well as neutrophil-to-lymphocyte ratio [ 30 , 31 ] and lymphocyte-to-monocyte ratio [ 32 ], were reported to significantly predict survival in patients suffering from RCC with tumor thrombus.…”

Neutrophils’ Extracellular Trap Mechanisms: From Physiology to Pathology

“…With the discovery of NETs, this link obtained a further player. In thrombi of renal cell carcinoma tumor and in stroke embolism, the NLR ratio correlated with the NET count [ 76 , 77 ].…”

Neutrophil extracellular traps primed intercellular communication in cancer progression as a promising therapeutic target

“…Based on the evidence of a cohort of 283 gastric adenocarcinoma (GAC) patients, it seemed that both the serum and plasma of blood samples could all be employed for NETs detection [ 108 ]. The immunohistochemical (IHC) technique was also used to measure NET formation in the primary tumor lesion or metastatic site of the tumor tissue sample [ 79 , 111 ]. The NET formation was identified as the neutrophils positive for the H3Cit signal [ 112 , 113 ].…”