Serum levels of the IL-6 family of cytokines predict prognosis in renal cell carcinoma (RCC)

Abstract

Purpose: An improved understanding of RCC immunology should shed further light on RCC tumor biology. Our objective was to study to what extent serum levels of the IL-6 family of cytokines at diagnosis were relevant to survival.

Methods: A total of 118 consecutively patients with RCC, in which the tumor was surgically removed at Haukeland University Hospital during the period from 2007 to 2010, were included. The patients were followed-up for 10 years. The morning before surgery blood was sampled and serum frozen, with levels of IL-6, IL-27, IL-31, OSM, CNTF, IL-6Rα and gp130 determined.

Results: Among patients with the highest quartile of IL-6 (> 8 pg/ml) (n = 29), six of nine who had metastasis at diagnosis had such high IL-6 values. Among presumed radically treated patients, a high IL-6 and IL-27 strongly predicted recurrence. In particular, the predictions among patients with large (diameter > 7 cm) tumors were excellent regarding both IL-6 and IL-27 values. High gp130 serum levels predicted an overall survival (OS) among RCC patients with large tumors. Patients with a high IL-6 exhibited a strong expression of IL-6 in endothelial- and vascular smooth muscle cells. Moreover, the level of intra-tumoral CD3-positive cells predicted survival.

Conclusions: IL-6 and IL-27 seem to play a role in RCC biology. IL-6 enables the pinpointing of metastatic condition at diagnosis, as well as together with IL-27, the predicting of survival and recurrence. Endothelial cells and vascular smooth muscle cells are both suggested as important sources of IL-6.

Keywords: IL-27; IL-6; Recurrence; Renal cell carcinoma; Survival; gp130.

Fig. 1

a The panels show low (left) and high (right) scores with tumor area CD3 staining lymphocytes. b The panels show renal tissue outside the tumor: to the left small arteries showing IL-6 positivity, and to the right interlobular artery showing a strong IL-6 expression in medial smooth muscle cells

Fig. 2

Kaplan–Meier recurrence curves from IL-6 and some family members, as analyzed by Luminex in the serum of assumed radically treated renal cell carcinoma (RCC) patients, sampled prior to surgery. The blue line represents a low value, whereas the red dotted line indicates a high value. Differences between the groups are examined in log-rank tests and presented with p values. a IL-6 recurrence prediction among 109 RCC patients (low (< 8 pg/ml): n = 86 and high (≥ 8 pg/ml): n = 23). b IL-27 prediction of recurrence in 91 RCC patients (low: n = 69 and high: n = 22). c–e Recurrence prediction of IL-6, IL-27, and gp130 in patients with large (> 7 cm) RCC tumors (low: three lower quartiles)/high: highest quartile). c IL-6: n = 35 (25/10). d IL-27: n = 26 (20/6). e gp130: n = 26 (22/4)

Fig. 3

Kaplan–Meier curves demonstrating disease-specific survival (DSS) prediction from IL-6, as well as related cytokines and receptors in pre-treatment RCC blood samples collected before surgical treatment. Analytes were measured simultaneously by Luminex technology. Low values are shown with a blue continuous line, and high values in red dotted lines. In addition, the graphs comprise p values from log-rank tests. a IL-6 DSS prediction among 118 RCC patients (low (< 8 pg/ml): n = 89 and high (≥ 8 pg/ml): n = 29). b IL-27 prediction of DSS in 97 RCC patients (low: n = 73 and high: n = 24). c and g DSS prediction from IL-6 in medium-sized (4.1–7 cm, n = 37) and large (> 7 cm, n = 42) RCC tumors. The highest quartile is denoted by high (n = 10/14), and the remaining values low (n = 27/23). d–f IL-27, gp130 and IL6R alpha prediction of DSS in patients harboring a large (> 7 cm) RCC tumor (n = 30). Quartiled analytes as above (high: n = 7/4/6 and low: n = 23/26/24)

Fig. 4

Overall survival (OS) Kaplan–Meier curve predictions from IL-6 and the family molecules IL-27 and gp130 by Luminex in serum collected before the surgical treatment of RCC patients. The blue continuous line visualizes low values (lower quartiles), with the high values in the red dotted line. Log-rank test p values are included in the separate windows. a IL-6 OS prediction among 118 RCC patients (low (< 8 pg/ml): n = 89 and high (≥ 8 pg/ml): n = 29). b IL-27 prediction of OS in 97 RCC patients (low: n = 73 and high: n = 24). c OS prediction from IL-6 in medium-sized [(4.1–7 cm, n = 37), n = 42] RCCs. Twenty-seven patients were designated as low, with 10 patients having a value within the highest quartile. d Prediction of OS from quartiled gp130 in RCC patients with a tumor size exceeding 7 cm (low: n = 26 and high: n = 4). e IL-6 OS prediction in large (> 7 cm, n = 42) RCC tumors; 28 high value patients and 14 with a low value

Fig. 5

ROC recurrence. Receiver operating characteristic (ROC) curves comparing recurrence prediction of IL-6, IL-27, and CRP in presumed radically treated (upper panel, n = 89) and all (lower panel, n = 95) RCC patients with such values, as analyzed in their serum ahead of surgical treatment. In both cases, 10 were regarded as positive. The right column shows results in patients with a tumor above 7 cm, of which nine had a positive annotation. The blue continuous line represents IL-6, the red dotted line is IL-27, and green semi-hatched line indicated by CRP

Fig. 6

Outcome predictions: a recurrence, b disease-specific survival, and c overall survival of total 28 RCC patients from immunohistochemical quantification of tumor CD3-positive T lymphocytes in surgical resection specimen. The expression levels were qualitatively scored by an experienced pathologist and further dichotomized by median value into high (All patients: n = 11/radically treated: n = 8) and low (n = 17 for all patients/n = 14 for radically treated). p values come from log-rank tests