HLA class-I genotyping to personalize Bacille Calmette–Guerin immunotherapy in bladder cancer

Bacille Calmette-Guerin (BCG) is the immunotherapy of choice for high-risk non-muscle invasive bladder cancer (BC), although recurrence eventually occurs in 50% of patients and 20% progress to advanced stages. This study evaluates the predictive value of human leukocyte antigen class-I (HLA-I) genotyping to guide BCG immunotherapy. HLA-I genotyping and expression of NK cell receptors in circulating T and NK lymphocytes was evaluated at diagnosis in 325 consecutive BC patients (151 treated with BCG and 174 with other therapies), 648 patients with other cancers and 23,250 healthy controls. Proliferation, cytotoxicity, and production of cytokines and intracellular nitric oxide (icNO) was assessed in peripheral blood mononuclear cells from these donors, selected based on their Bw4 genotype, after stimulation <i>in vitro</i> with anti-CD3/CD28 or BCG. HLA-A*11, HLA-B*07 and HLA-B*18 allotypes were associated with favorable outcomes after BCG therapy (longer progression-free and overall survival), whereas HLA-B*44 and other KIR3DL1 Bw4 ligands were associated with unfavorable outcomes. Although Bw4 ligands were associated with better NK cell education <i>in vivo</i> (CD226-upregulation, KIR3DL1 downregulation and stronger NK cytotoxic capacity), they were also associated with weaker NK cell proliferation, and lower IL-1β, IL-6, and icNO production after BCG stimulation <i>in vitro</i>, revealing an inhibitory role of KIR3DL1. Mechanisms by which KIR3DL1/Bw4 interaction interferes with BCG-induced NK cell proliferation and the production of cytokines and icNO, warrant further investigation. HLA-I genotyping should be investigated as a useful biomarker to personalize BCG immunotherapy in BC.