Molecular Characterization of Defective Antigen Processing in Human Prostate Cancer
- 15 February 1995
- journal article
- research article
- Published by Oxford University Press (OUP) in JNCI Journal of the National Cancer Institute
- Vol. 87 (4) , 280-285
- https://doi.org/10.1093/jnci/87.4.280
Abstract
Background: Gene-modified tumor cell vaccines have shown efficacy in animal models of malignancy, including prostate cancer. Class I major histocompatibility complex (MHC) assembly and function in the cellular targets of such therapies is pivotal in determining the efficacy of specific cytokine-secreting tumor vaccines. Purpose To help guide development of genetically engineered vaccine therapy for human prostate cancer, potential immune resistance pathways were evaluated by analysis of class I MHC assembly in prostate cancer cells. Method: Class I MHC assembly in metastasis-derived human prostate cancer cell lines (LNCaP, PPC-1, DU-145, PC-3, and TSU) and a normal prostate-derived cell line (TP-2) were characterized by phenotypic, molecular, and functional assays. Assembled class I MHC and antigen was measured by flow cytometry; mRNA levels of assembly components (class I MHC heavy chain,; β2-microglobulin, and the antigen transporter gene product TAP-2) were determined; and antigen processing was measured with a chimeric reconstituted system using vaccinia vectors. Restoration of antigen processing was attempted by interferon gamma stimulation and by transfection with mouse class I MHC heavy-chain cDNA. Results : Assembled class I MHC was underexpressed in two (LNCaP and PPC-1) of five prostate cancer cell lines compared with normal prostate-derived controls. PPC-1 cells underexpressed TAP-2 mRNA despite abundant class I MHC and β2-microglobulin message. Induction of TAP-2 by interferon gamma indicated that coding sequences for TAP-2 message were present in PPC-1. Resistance to cytotoxic T lymphocytes (CTL) lysis showed a functional defect in antigen transport by PPC-1 cells; reversal of the molecular defect with interferon gamma led to restoration of functional antigen processing. In contrast, LNCaP cells had competent antigen transport but deficient class I MHC heavy-chain function despite abundant class I MHC RNA; though refractory to stimulation by interferon gamma, this defect responded to transfection of class I MHC heavy-chain cDNA. Conclusions : Metastatic prostate cancer cells can escape T-cell recognition via divergent mechanisms of defective class I MHC assembly. The specific under-expression of TAP-2 gene product in PPC-1 cells contrasts with prior studies of TAP gene underexpression in lung cancer (which concurrently underexpressed class I MHC heavy chain) and provides evidence for a regulatory pathway controlling TAP-2 gene expression in human cancers that may not affect class I MHC heavy-chain expression- Implications:In clinical application of gene therapy for prostate cancer, these findings provide a rationale for focusing on strategies that can circumvent sole reliance on class I MHC-mediated tumor cell recognition by CTL. [J Natl Cancer Inst 87: 280–285, 1995]Keywords
This publication has 17 references indexed in Scilit:
- Interleukin‐2 transfected prostate cancer cells generate a local antitumor effect in vivoThe Prostate, 1994
- In vivo priming of two distinct antitumor effector populations: the role of MHC class I expression.The Journal of Experimental Medicine, 1994
- Regression of bladder tumors in mice treated with interleukin 2 gene-modified tumor cells.The Journal of Experimental Medicine, 1993
- Identification of human cancers deficient in antigen processing.The Journal of Experimental Medicine, 1993
- Treatment and Prevention of Rat Glioblastoma by Immunogenic C6 Cells Expressing Antisense Insulin-Like Growth Factor I RNAScience, 1993
- A nonimmunogenic sarcoma transduced with the cDNA for interferon gamma elicits CD8+ T cells against the wild-type tumor: correlation with antigen presentation capability.The Journal of Experimental Medicine, 1992
- Treatment of Established Renal Cancer by Tumor Cells Engineered to Secrete Interleukin-4Science, 1991
- Transport Protein Genes in the Murine MHC: Possible Implications for Antigen ProcessingScience, 1990
- A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathwayNature, 1990
- Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transportersNature, 1990