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Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance

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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.

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Abbreviations

APM:

Antigen presentation machinery

B2M:

Beta-2-microglobulin

BH:

Benign prostate hyperplasia

cDNA:

Complementary DNA

CTL:

Cytotoxic T lymphocyte

DNA:

Deoxyribonucleic acid

FACS:

Fluorescence-activated cell sorter/sorting

FCS:

Fetal calf serum

FITC:

Fluorescein isothiocyanate

HLA:

Human histocompatibility leukocyte Ag

HPV:

Human papillomavirus

HRP:

Horseradish peroxidase

IFN:

Interferon

IHC:

Immunohistochemistry

LOH:

Loss of heterozygosity

mAb:

Monoclonal Ab

MFI:

Mean fluorescence intensity

PC:

Prostate cancer

Ph:

Phenotype

PNI:

Perineural invasion

PSA:

Prostate-specific antigen

RT-PCR:

Reverse transcriptase polymerase chain reaction

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Acknowledgments

We would like to thank Svitlana Zinchenko for technical assistance. This work was supported by grants co-financed by FEDER (Fondo Europeo de Desarollo Regional/European Regional Development Fund, European Union) and by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion y Fomento de la Investigacion grants as a part of the Plan Nacional de I + D + I 2008–2011 (CP03/0111, PI12/02031, PI08/1265, PI11/01022, PI11/01386, RETIC RD 06/020, RD09/0076/00165) and Plan Nacional de I + D + I 2013–2016 (PT13/0010/0039, PI 14/01978); as well as by Junta de Andalucía (Groups CTS-143, CTS-695, CTS-3952, CVI-4740, and PI 09/0382 Grant); and by the European Union project ENACT (European Network for the identification and validation of antigens and biomarkers in cancer and their application in clinical tumor immunology, LSHC-CT-2004-503306). N. Aptsiauri was supported by Miguel Servet and I3 SNS contracts from Fundación Progreso y Salud of the Junta de Andalucia and Instituto de Salud Carlos III. FJ. Carretero was supported by a pre-doctoral fellowship of the FPU program (Formación de profesorado Universitario) from the Ministry of Education of Spain.

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Author notes

  1. Victoria Adams & Stephen Ward

    Present address: Cell Therapy Catapult Limited, NIHR Biomedical Research Centre, Guy’s Hospital, London, UK

Authors and Affiliations

  1. 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

    Ana Belen del Campo, Rosa Mendez, Francisco Ruiz-Cabello, Federico Garrido & Natalia Aptsiauri

  2. UGC Urología del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Granada, Spain

    Jose Francisco Flores-Martín & Jose Manuel Cozar

  3. UGC Anatomía Patológica del Complejo Hospitalario Universitario de Granada, Instituto de Investigación Biosanitaria ibs. Granada, Granada, Spain

    Cesar García-Lopez

  4. Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain

    Francisco Javier Carretero, Rosa Mendez, Teresa Cabrera, Francisco Ruiz-Cabello & Federico Garrido

  5. Onyvax, Ltd, St. George’s Hospital, University of London, London, UK

    Victoria Adams & Stephen Ward

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  1. Francisco Javier Carretero
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  2. Ana Belen del Campo
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  9. Teresa Cabrera
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  10. Francisco Ruiz-Cabello
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  11. Federico Garrido
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Correspondence to Natalia Aptsiauri.

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Carretero, F.J., del Campo, A.B., Flores-Martín, J.F. et al. Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance. Cancer Immunol Immunother 65, 47–59 (2016). https://doi.org/10.1007/s00262-015-1774-5

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