PLASMA LEVELS OF THE CO-STIMULATORY MOLECULE B7 HOMOLOG 1 (B7-H1) IS SIGNIFICANTLY INCREASED IN PATIENTS WITH COLORECTAL CANCER
H M C Shantha Kumara*1, Dasuni Niyagama Gamage1, Neil Mitra1, Hiromichi Miyagaki2, Carl S. Winkler1, Jaspreet Sandhu1, Xiaohong Yan1, Vesna Cekic1, Nipa Gandhi1, Richard L. Whelan1
1Deaprtment of Surgery, Room 3B-61, Mount Sinai West Hopital, New York, NY; 2Department of Surgery, 1179-3 Nagasonecho, Kita-ku, Sakai-shi,Osaka Rousai Hospital, Osaka, ÅŒsaka-fu, Japan
Introduction: The co-stimulatory molecule B7 homolog 1 (B7-H1), a transmembrane glycoprotein, is a ligand for PD-1, an immune inhibitory receptor found on activated lymphocytes. PD-1 expression is upregulated on tumor infiltrating lymphocytes (TIL's), and B7-H1 expressed on cancer cells may inhibit TIL's infiltration, activation and proliferation. B7H1 in endothelial cells is induced by inflammatory cytokines IFN-gamma and TNF. Aberrant B7-H1 expression has been reported in activated immune cells, macrophages and colorectal cancer (and other tumors). B7-H1 silencing with siRNA inhibits tumor cell proliferation/invasion. Plasma levels of free (unbound) B7H1 in colorectal cancer patients have not been well studied. This study's purpose was to compare preoperative (PreOp) plasma B7H1 levels in colorectal cancer and benign colonic pathology patients.
Method: PreOp plasma samples from colorectal cancer and benign colonic pathology patients enrolled in an IRB approved data/plasma bank who underwent elective resection were eligible. Clinical, demographic and final pathological data were prospectively gathered. Plasma B7H1 levels were determined via ELISA in duplicate and are reported as median ±95% CI (ng/ml). The expressions levels of B7H1 in self-paired normal and cancer colorectal specimens were assessed by QRT-PCR. The candidacy of B7H1 as a diagnostic marker for colorectal cancer was validated by the receiver operating characteristic (ROC) curve and by the area under the ROC curve (AUC) results. The Mann-Whitney test was used for statistical analysis, (significance (sig) p<0.05).
Results: The study population consisted of 108 colorectal cancer (75% colon, 25% rectal) and 100 and benign colonic pathology patients (adenoma 48%, diverticulitis 47%, other 5%). Colorectal cancer patients were older (66 vs 60 years) but the male/female ratios were similar. The median PreOp plasma B7H1 level was higher in cancer patients (49.3, CI: 45.2, 52.6) than in the benign colonic pathology group (44.6, CI: 39.5, 47.6, p<0.001). The colorectal cancer stage distribution was: Stage-1, 28%; Stage-2, 28%, Stage-3, 37%, Stage- 4, 7%. There was no relationship found between cancer stage and B7H1 levels. Thirty one percent of the colorectal cancer tumors tested (5/16) showed elevated B7H1 expression vs. paired normal tissue. The AUC value for ROC curve was 0.6369(sensitivity 80 %, specificity 43%).
Conclusion: The median plasma B7H1 level in the setting of colorectal cancer was 11% higher than noted in the benign colonic pathology group (p<0.001). AUC values suggest B7H1 may have value in combination with other markers as a prognostic marker panel for colorectal cancer. The source of the additional B7H1 is likely the tumor and immune cells activated via inflammatory pathways. Further study with larger populations of control and colorectal cancer patients is warranted.
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