A Three-Dimensional Tumor Cell Defect in Activating Autologous CTLs Is Associated with Inefficient Antigen Presentation Correlated with Heat Shock Protein-70 Down-Regulation ⁽¹⁾

Room : 601

Time : 2003/10/13  2:00-3:00 p.m.

Speaker : 王琳雅

Commentator : 蘇五洲 老師

    Tumors form three-dimensional structures in vivo, which can escape from immune system. To investigate the influence of tumor cells architecture on T-cell activation, the authors used an autologous human model based on IGR-Heu carcinoma cell line as targets for cytotoxic T lymphocytes (CTLs). The tumor cell line was grown in vitro as either standard 2-dimensinal (2D) monolayer or 3-dimensional (3D) spheroid ⁽²⁾. The CTL clone was able to lyse the autologous IGR-Heu after specific recognition of an HLA-A2/mutated α-actinin-4 peptide complex. After co-cultured the tumor cells with CTLs, changes in the architecture of target cells from 2D to 3D induced a dramatic decrease in their capacity for stimulating CTLs by measuring cytokine production. The functional alteration were attributable neither to MHC class I expression nor to tumor Ag down-regulation, because IGR-Heu, cultured as two- or three-dimensional, expressed similar levels of HLA-A2 andα-actinin-4. Moreover, incubation of 3D cells with exogenous α-actinin-4 peptide completely restored cytokine release by CTL. This defective Ag presentation correlated with heat shock protein-70 (hsp70) down-regulation in 3D tumors compared with 2D cells. Hsp70 is a part of the endogenous pathway of antigen presentation by MHC classs I ⁽³⁾. Furthermore, transfection of the tumor cells with hsp70 cDNA completely restored the Ag-presenting of spheroid and cytokine production by T cells. These results suggest that hsp70 down-regulation in 3D cells may cause tumor resistance to the immune response.

References:

1.        Virginie D., et al. Cancer Res., 63, 3682–3687, 2003.

2.        Virginie D., et al. Int. J. Cancer, 98: 51–56, 2002.

3.        Zihai, L., et al. Curr. Opin. Immunol., 14: 45–51, 2002.