Abstract
Background and Aims: Dysfunction of the host immune system in cancer patients can be due to a number of factors, including secretion of tumor-derived immunosuppressive factors or induction of immune tolerance against tumor-specific antigens. Several studies suggest that suppression of tumor-associated antigen reactivates lymphocytes by CD4(+) CD25(+) regulatory T (T-reg) cells. This study was designed to evaluate whether CD4(+)CD25(+) T-reg cells in chronic liver disease and hepatocellular carcinoma (HCC) patients exhibit an expanded T-reg pool and to correlate it with liver tumor markers and grading.
Methods: Blood samples were collected from 20 patients with cirrhotic liver disease (CLD), 15 HCC patients and 10 healthy control subjects. Alpha feto-protein (AFP), HBV and HCV antibodies were detected by EIA. HCV was confirmed by immunoblotting and RT-PCR. To evaluate HCC grading, abdominal ultrasound guided liver biopsy was done. Patients were categorized into moderately differentiated (grade II) and poorly differentiated (grade III) groups. Cytometric analysis of CD4(+)CD25(+) T-reg cells in PBMCs was performed using anti-CD3, anti-CD4, anti-CD25, anti-CD45RA, and IgG-isotype control (FITC and PE).
Results: Both CLD and HCC groups were 80% positive for HCV while only 20% of CLD and 11% of HCC patients were positive for HBV. The mean percentage of CD4(+)CD25(+)T cell population demonstrated a highly significant increase in comparing HCV to HCC patients [2.47 +/- 0.66 vs. 8.96 +/- 1.38 (P < 0.001)] and when comparing both group to controls [1.15 +/- 0.5 (P < 0.01)]. Nine HCC patients were in grade II while 6/15 were in grade III. Their mean CD4(+)CD25(+) T cells percentage was 9.12 +/- 1.52 and 8.73 +/- 1.33, respectively. A negative correlation was found between mean CD4(+)CD25(+) T cells percentage and AFP serum level in HCC patients (r = 0.923) while T-reg cells with patients tumor grades (II and III) (r = 0.474 and 0.582, respectively). CLD showed a significant correlation with AFP level (r = 0.962).
Conclusions: Tumor specific T-reg cells may limit the efficacy of anti-tumor response. T-reg cells correlate properly with the unique marker AFP and with tumor grades. Better understanding of the underlying mechanism of T-reg regulation or of the strategy for controlling T-reg cells may lead to effective HCV immunotherapy and enhancing immunity against cancer.