Background: MICA/B (major histocompatibility antigen related chain A and B) are two stress inducible cell surface molecules that act as ligands for the immune receptor NKG2D expressed on activated NK and T cells. MICA/B are broadly expressed in a variety of malignancies including pancreatic cancer. MICA/B expression in pancreatic cancer cell lines correlates with their sensitivity to the cytotoxic activity of NK-92 cells, a natural killer cell line which is now being tested in clinical trials for cancer. Hypothesis: Recent studies showed that uric acid can function as a novel “Danger” signal in injured cells to alert the immune system. We hypothesize that radiation or DNA damaging drugs gemcitabine or 5-FU, that induce uric acid accumulation in DNA-damaged pancreatic cancer cells, can induce MICA/B expression. Methods: Panc-1 cells were treated with uric acid (250 μg/ml), 5-FU (10 μM), gemcitabine (2 μM), and radiation (40 Gy) in the absence or presence of allopurinol (AP) (500 μg/ml) and analyzed for MICA/B expression by fluorescein-activated cell sorting (FACS) with an anti-MICA/B mAb. Results: Uric acid, 5-FU, gemcitabine, and radiation increased MICA/B expression on Panc-1 cells, as demonstrated by a right shift of MICA/B peak (green line), compared to the untreated control. AP (a purine metabolism pathway antagonist) alone had no effect on MICA/B expression. AP blocked MICA/B expression in 5-FU and gemcitabine-treated and radiated Panc-1 cells, as shown by a shift of the MICA/B peak to the left (pink line). Conclusion: Radiation and DNA damaging drugs induce MICA/B expression in Panc-1 cells. Since this is blocked by allopurinol, it seems that induction of MICA/B expression is due to uric acid accumulation in DNA-damaged cells. Since MICA/B enhances NK-92 cell-mediated cytotoxicity, this study suggests that the effects of radiation and chemotherapy on pancreatic cancer can be augmented by immunotherapy.