CD26-Related Serum Biomarkers: sCD26 Protein, DPP4 Activity, and Anti-CD26 Isotype Levels in a Colorectal Cancer-Screening Context

Abstract

Current screening trials are showing reduction in colorectal cancer incidence and mortality. However, participation rates are often low, and blood-based tests could complement existing screening strategies. CD26 protein (sCD26) and its dipeptidyl peptidase IV (DPP4) enzymatic activity in circulation have been proposed as biomarkers for colorectal cancer and other diseases. However, changes in sCD26 and DPP4 levels show complex degrees of correlation, and their physiological or pathophysiological role is unclear. The aim of this study was to analyse if anti-CD26 autoantibodies are related to sCD26 and DPP4 and to determine their relevance in a context of colorectal cancer screening for complementing the value of sCD26 and DPP4 as biomarkers. These biomarkers were measured in a large prospective cohort (n=497, except the anti-CD26 antibodies, evaluated in 125 samples) that included a subgroup of individuals that were positive for the faecal immunological occult blood test (FIT) (n=86) and underwent a colonoscopy (n=47). We confirmed for the first time higher DPP4 activity in men compared to women (Student’s t test, p=0.002), though this difference between sexes was not seen for serum sCD26 protein. These biomarkers correlated (R=0.246, p=0.003) only in women. Correlations were found between anti-CD26 isotypes but not with DPP4 activity or sCD26 concentration, except for a negative correlation only in men between anti-CD26 IgA isotype and sCD26 (R=−0.232, p=0.044), and an almost significant negative correlation between anti-CD26 IgG and sCD26 limited to FIT-positive men. Interestingly, patients with advanced adenomas displayed the most elevated mean levels of anti-CD26 IgA, IgM, and particularly IgG (Mann-Whitney U test, p=0.030) in comparison with the other FIT positives without adenomas, and these levels did not correlate with sCD26 or its DPP4 activity. Our preliminary results suggest that the combination of these measures using sex as confounder could perhaps be used as biomarkers for colorectal disease. It also suggests that events affecting the gut influence the levels of anti-CD26 antibodies, which show little or no effect in antigen clearance. These findings should be confirmed in a larger cohort of individuals with colonoscopy. The physiological origin of the sex differences observed should be further addressed.

Risk-Predictive and Diagnostic Biomarkers for Colorectal Cancer; a Systematic Review of Studies Using Pre-Diagnostic Blood Samples Collected in Prospective Cohorts and Screening Settings

“…A total of 27 studies included data potentially stemming from a general screening setting, of which four were excluded due to small sample size or non-general screening [24][25][26][27]. Of the remaining 23 studies, 17 presented results for colorectal cancer, and 15 presented results for advanced adenoma.…”

Immunoglobulin A, an Active Liaison for Host-Microbiota Homeostasis

“…As with any cancer, early detection is vital to reduce mortality because treatment can immediately begin after diagnosis. Several studies have investigated autoreactive antibodies with special emphasis on IgA as a prominent CRC screening tool [192][193][194]. In particular, IgA reactive to the tumor associated antigen carcinoembryonic antigen (CEA) has been an important signature for CRC patients.…”

Serum soluble CD26/DPP4 titer variation is a potential prognostic biomarker in cancer therapy with a humanized anti-CD26 antibody

“…A correlation between baseline serum sCD26 titer and clinical effectiveness of therapy has been described for patients with urothelial, gastric, pancreatic, thyroid, or lung cancer [9][10][11][12][13][14]. Serum sCD26 titer variation after colon cancer surgery was also reported to be a predictive biomarker for risk of recurrence or metastasis [15][16][17]. In addition, treatment with the DPP4 inhibitor sitagliptin after surgery for colorectal or lung cancer in patients with diabetes was associated with greater overall survival than treatment with other diabetic medications [18], suggesting that sCD26/DPP4 may have a role in regulating anti-tumor activity.…”