title: Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance.
abstract: Reduced expression of HLA class I is an important immune escape mechanism from cytotoxic T cells described in various types of malignancy. It often correlates with poor prognosis and resistance to therapy. However, current knowledge about the frequency, underlying molecular mechanisms, and prognostic value of HLA class I and II alterations in prostate cancer (PC) is limited. Immunohistochemical analysis demonstrated that 88 % of the 42 studied cryopreserved prostate tumors have at least one type of HLA alteration as compared to adjacent normal prostate epithelium or benign hyperplasia. Total loss of HLA-I expression found in 50 % of tumors showed an association with increased incidence of tumor relapse, perineural invasion, and high D'Amico risk. The remaining HLA-I-positive tumors demonstrated locus and allelic losses detected in 26 and 12 % of samples, respectively. Loss of heterozygosity at chromosome 6 was detected in 32 % of the studied tumors. Molecular analysis revealed a reduced expression of B2M, TAP2, tapasin and NLRC5 mRNA in microdissected HLA-I-negative tumors. Analysis of twelve previously unreported cell lines derived from neoplastic and normal epithelium of cancerous prostate revealed different types of HLA-I aberration, ranging from locus and/or allelic downregulation to a total absence of HLA-I expression. The high incidence of HLA-I loss observed in PC, caused by both regulatory and structural defects, is associated with more aggressive disease development and may pose a real threat to patient health by increasing cancer progression and resistance to T-cell-based immunotherapy.
authors.affiliation: Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Carretero
authors.affiliation: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Avda Fuerzas Armadas 2, 18014, Granada, Spain.
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Del Campo
authors.affiliation: UGC Urología del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Granada, Spain.
authors.forename: Jose Francisco
authors.initials: JF
authors.lastname: Flores-Martín
authors.affiliation: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Avda Fuerzas Armadas 2, 18014, Granada, Spain.|Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Mendez
authors.affiliation: UGC Anatomía Patológica del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Granada, Spain.
authors.forename: Cesar
authors.initials: C
authors.lastname: García-Lopez
authors.affiliation: UGC Urología del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Granada, Spain.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Cozar
authors.affiliation: Onyvax, Ltd, St. George's Hospital, University of London, London, UK.|Cell Therapy Catapult Limited, NIHR Biomedical Research Centre, Guy's Hospital, London, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Adams
authors.affiliation: Onyvax, Ltd, St. George's Hospital, University of London, London, UK.|Cell Therapy Catapult Limited, NIHR Biomedical Research Centre, Guy's Hospital, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ward
authors.affiliation: Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Cabrera
authors.affiliation: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Avda Fuerzas Armadas 2, 18014, Granada, Spain.|Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Cabello
authors.affiliation: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Avda Fuerzas Armadas 2, 18014, Granada, Spain.|Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Garrido
authors.affiliation: Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Avda Fuerzas Armadas 2, 18014, Granada, Spain. naptsiauri@hotmail.com.
authors.forename: Natalia
authors.initials: N
authors.lastname: Aptsiauri
mesh_terms: D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D009364:Neoplasm Recurrence, Local; D011471:Prostatic Neoplasms / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin
keywords: Antigen presentation; Beta-2-microglobulin; Clinical prognosis; HLA molecules; Human prostate cancer; Tumor recurrence