Bacillus Calmette‐Guerin immunotherapy of bladder cancer induces selection of human leukocyte antigen class I‐deficient tumor cells

Bacillus Calmette‐Guerin (BCG) immunotherapy is a standard treatment for high‐risk non‐muscle‐infiltrating bladder cancer patients. Although the outcomes are good, cancer relapse is observed in around 40% of patients. We present the comparative analysis of human leukocyte antigen (HLA) class I expression in recurrent bladder tumors in patients treated with mitomycin or BCG. HLA class I expression was analyzed by RT‐Q‐PCR and immunohistochemical techniques. Loss of heterozygosity (LOH) was determined by microsatellite amplification of markers in chromosome 6 and 15. More profound alterations in HLA class I expression were found in post‐BCG recurrent tumors than in pre‐BCG lesions, whereas mitomycin treatment did not change the HLA class I expression pattern. Post‐BCG recurrent tumors also showed a higher incidence of structural defects underlying altered HLA class I expression. We hypothesize that the immunotherapy‐activated immune system recognizes and eliminates tumor cells with reversible (“soft”) HLA class I changes but not transformed cells with additional, irreversible (“hard”) alterations. To our knowledge, this is the first clinical evidence of immunotherapy‐induced immunoselection of HLA class I loss tumor variants in bladder cancer, although the study involved a small number of patients.