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.
Department of Clinical Analysis, Virgen de las Nieves University Hospital, and Department of Biochemistry, Molecular Biology III and Immunology, University of Granada, Spain.
Rafael
R
Carretero
Teresa
T
Cabrera
Hernani
H
Gil
Pablo
P
Saenz-Lopez
Isabel
I
Maleno
Natalia
N
Aptsiauri
Jose M
JM
Cozar
Federico
F
Garrido
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000627:therapeutic use; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000276:immunology / Q000378:metabolism; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000628:therapy*
D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; D001500:BCG Vaccine; D015395:Histocompatibility Antigens Class I; D012333:RNA, Messenger; D016685:Mitomycin