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.

DOI: 10.1007/s00262-015-1774-5

Cite this paper

@article{Carretero2015FrequentHC, title={Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance}, author={Francisco Javier Carretero and Ana Belen del Campo and Jos{\'e} Francisco Flores-Mart{\'i}n and Rosa Mar{\'i}a M{\'e}ndez and Cesar G. Garc{\'i}a-L{\'o}pez and Jos{\'e} Manuel C{\'o}zar and Victoria Adams and Stephen Ward and Teresa Cabrera and Francisco Javier Montes Ruiz-Cabello and Federico F Garrido and Natalia Aptsiauri}, journal={Cancer Immunology, Immunotherapy}, year={2015}, volume={65}, pages={47-59} }