The Expression Level of Ligands for Natural Killer Cell Receptors Predicts Response to Bacillus Calmette-Guerin Therapy: A Pilot Study

Purpose: Up to 90% of patients with high grade superficial bladder tumors experience tumor recurrence and up to 50% have progression despite bacillus Calmette-Guerin treatment. Natural killer cells have a major role in the mechanism of the response to bacillus Calmette-Guerin but the exact mechanisms are still elusive. The recently discovered natural cytotoxicity receptors are linked to the host response to viral infection and to cancer. We tested the hypothesis that tumor expression of natural cytotoxicity receptor ligands can serve as a predictive factor for the response to intravesical bacillus Calmette-Guerin in patients with nonmuscle invasive, high grade bladder cancer. Materials and Methods: We developed a histochemical staining method for analysis of the ligands of the 3 known natural cytotoxicity receptors NKp30, NKp44 and NKp46 using genetically engineered fusion proteins and an automated image analysis system. We examined formalin fixed, paraffin embedded sections of specimens of transurethral bladder tumor resection from patients with primary, nonmuscle invasive, high grade bladder cancer who were subsequently treated with bacillus Calmette-Guerin. We compared natural cytotoxicity receptor ligand expression to the response to bacillus Calmette-Guerin immunotherapy. Results: Six of 17 patients (35%) had recurrence despite bacillus Calmette-Guerin treatment. Primary tumors from favorably responding patients expressed higher levels of ligands for all 3 fusion proteins (NKp30, NKp44 and NKp46 p = 0.0026, 0.027 and 0.044, respectively). Conclusions: Bacillus Calmette-Guerin resistant, high grade, nonmuscle invasive bladder tumors express significantly lower levels of ligands of all 3 natural cytotoxicity receptors compared with bacillus Calmette-Guerin responsive tumors. This suggests that down-regulation of these ligands facilitates escape from the bacillus Calmette-Guerin effect. Furthermore, analysis of ligand expression, which can be performed on formalin fixed, paraffin embedded sections, may serve as a new predictive assay for the response to bacillus Calmette-Guerin.