High Level of Anaphylatoxin C5a Predicts Poor Clinical Outcome in Patients with Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC), arising from renal tubular epithelial cells, accounts for approximate 2–3% of all malignancies in adults1. In China, over 54 out of 100,000 people are diagnosed with RCC every year2, and most of the cases (70–85%) are clear cell RCC (ccRCC), histologically3. Although incidental RCC has taken up more than 50% of all RCCs due to the widespread use of abdominal imaging4,5, 25–30% of the patients still have the initial diagnosis with metastasis6. Moreover, another 20% of the patients will have a relapse and develop metastatic RCC (mRCC) after curative nephrectomy7. Characterized by the resistance to radiotherapy and chemotherapy, mRCC exhibits an extremely poor prognosis8,9, which makes the predicting system more important. Currently, some clinical or pathological predicting systems are used to predict outcomes of RCC patients. TNM stage and Fuhrman grade are traditional, but the most common used systems. Meanwhile, integrated systems, including Mayo Clinic stage, size, grade and necrosis (SSIGN) score and University of California integrated Staging System (UISS), are also clinically employed10,11. With these predicting systems, however, accurate prediction remains difficult, thus better or novel predictors of survival of RCC are needed10,12. Inflammatory microenvironment plays a vital role during tumor initiation and progression13. Renal cell carcinoma also exhibits a strong connection with hypoxia and enhanced inflammatory signaling14. Anaphylatoxin C5a, including C5a itself and its spliced form C5adesArg- being removed of the C-terminal arginine, is another potent pro-inflammatory peptide produced in the process of complement activation15. Growing evidence has suggested that C5a may serve as a negative wrecker in tumor initiation and progression by modulating microenvironment16,17. Additionally, it is reported that high level of C5a receptor (C5aR) is associated with poor clinical outcome in lung cancer18, while no investigations have focused on the prognostic function of C5a. Therefore, we are curious about the association between C5a and ccRCC patients’ prognosis and speculate that C5a could probably function as a prognostic marker. In this study, we sought to identify the clinical and prognostic value of C5a in ccRCC by immunohistochemical staining. We analysed the association of tumoral C5a level with clinicopathological characteristics and clinical outcomes (OS and RFS). Moreover, C-index was applied to explore the effect of tumoral C5a on prediction accuracy by incorporating it with traditional systems.