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Association of HLA class I antigen abnormalities with disease progression and early recurrence in prostate cancer

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Abstract

Defects in HLA class I antigen processing machinery (APM) component expression often have a negative impact on the clinical course of tumors and on the response to T cell-based immunotherapy. Since only scant information is available about the frequency and clinical significance of HLA class I APM component abnormalities in prostate cancer, the APM component expression pattern was analyzed in 59 primary prostate carcinoma, adjacent normal tissues, as well as in prostate carcinoma cell lines. The IFN-γ inducible proteasome subunits LMP2 and LMP7, TAP1, TAP2, calnexin, calreticulin, ERp57, and tapasin are strongly expressed in the cytoplasm of normal prostate cells, whereas HLA class I heavy chain (HC) and β2-microglobulin are expressed on the cell surface. Most of the APM components were downregulated in a substantial number of prostate cancers. With the exception of HLA class I HC, TAP2 and ERp57 not detectable in about 0.5% of tumor lesions, all other APM components were not detected in at least 21% of lesions analyzed. These APM component defects were associated with a higher Gleason grade of tumors and an early disease recurrence. Prostate carcinoma cell lines also exhibit a heterogeneous, but reduced constitutive APM component expression pattern associated with lack or reduced HLA class I surface antigens, which could be upregulated by IFN-γ. Our results suggest that HLA class I APM component abnormalities are mainly due to regulatory mechanisms, play a role in the clinical course of prostate cancer and on the outcome of T cell-based immunotherapies.

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Abbreviations

APM:

Antigen processing machinery

AR:

Androgen receptor

ATCC:

American tissue culture collection

β2-m:

β2-Microglobulin

CTL:

Cytotoxic T lymphocyte

FCS:

Fetal calf serum

HC:

Heavy chain

IFN:

Interferon

LMP:

Low molecular weight protein

mAb:

Monoclonal antibody

MHC:

Major histocompatibility complex

PC:

Prostate carcinoma

PSA:

Prostate-specific antigen

RCC:

Renal cell carcinoma

TA:

Tumor antigen

TAP:

Transporter associated with antigen processing

tpn:

Tapasin

TMA:

Tissue microarray

TNF:

Tumor necrosis factor

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Acknowledgments

We would like to thank Rudolf Jung for excellent technical support and Claudia Stoerr and Sylvi Magdeburg for the excellent secretarial help in preparing the manuscript. This work is supported by a grant of the Deutsche Forschungsgemeinschaft SE-581/10-1, 2 (BS) and by PHS grants RO1CA110249 awarded by the National Cancer Institute, DHHS and DOD grant 7-01-0096 (SF).

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Authors and Affiliations

  1. Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112, Halle, Germany

    Barbara Seliger, Diana Handke & Anja Mueller

  2. Institute of Pathology, University Hospital Erlangen, Erlangen, Germany

    Robert Stoehr & Arndt Hartmann

  3. Departments of Surgery, of Immunology and of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Soldano Ferrone

  4. Department of Urology, University Hospital, Erlangen, Germany

    Bernd Wullich

  5. Institute of Pathology, Ruhr-University of Bochum, Bochum, Germany

    Andrea Tannapfel

  6. Institute of Pathology, University of Regensburg, Regensburg, Germany

    Ferdinand Hofstaedter

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  1. Barbara Seliger
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Correspondence to Barbara Seliger.

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Seliger, B., Stoehr, R., Handke, D. et al. Association of HLA class I antigen abnormalities with disease progression and early recurrence in prostate cancer. Cancer Immunol Immunother 59, 529–540 (2010). https://doi.org/10.1007/s00262-009-0769-5

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