IMPLICATIONS OF HEME OXYGENASE-1 EXPRESSION IN PROSTATE CANCER IMMUNOMODULATION

NICOLÁS O. AMIANO; NICOLÁS ANSELMINO; RODRIGO HERNÁNDEZ DEL PINO; GERALDINE GUERON; VERÓNICA E. GARCÍA; ELBA S. VAZQUEZ

Capital Federal

Congreso; I Meeting LASID FAIC SAI; 2015

Abstract: Background: Heme oxigenase-1 (HO-1) is a homeostatic enzyme with anti-oxidative and anti-inflammatory functions. It is implicated in apoptosis and immunomodulation. PD-L1/PD-1 signaling is a T cell co-inhibitory pathway and expression of both molecules has been detected in prostate cancer (PCa) microenvironment, likely impairing the antitumor immunity. Nevertheless, the association between HO-1 and PD-L1/PD-1 pathway in PCa is not elucidated. Here we studied the effect of HO-1 on the expression of surface molecules involved in tumor escape. Methods: PC3 cells and human Peripheral Blood Mononuclear Cells (PBMCs) were treated +/- hemin (HO-1 inducer, 50uM, 24h) and/or IFN-gamma (2ng/ml, 24h). Cells were harvested and the levels of PD-L1, FasL, PD-1, and apoptosis were determined by flow cytometry. HO-1 and IFN-gammaR1 relative gene expression were analyzed by qRT-PCR. Results: HO-1 induction significantly reduced PD-L1 and FasL expression in PC3 cells (18±7% and 20±9%, respectively). This effect on PD-L1 was also observed when cells overexpressing HO-1 were treated with IFN-gamma (17±3%). However, HO-1 overexpression significantly increased the percentage of CD4+PD-1+ and CD4+PD-L1+ cells (16,9±0,1% and 7,2±1,0%) compared with controls (9,2±1,2% and 4,0±1,2%), similar to cells treated with hemin plus IFN-gamma. This enhancement was also detected in antigen presenting cells (monocytes). HO-1 induction in PC3 significantly reduced the apoptosis levels (38±8%) when cultured in serum free medium, effect that could not be reversed under IFN-gamma treatment. Conclusions: Our results suggest that HO-1 would be involved in the modulation of the immune response against the tumor.