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A Three-Dimensional Tumor Cell Defect in Activating Autologous CTLs Is Associated with Inefficient Antigen Presentation Correlated with Heat Shock Protein-70 Down-Regulation¹

Centre National de la Recherche Scientifique, Laboratoire d’immunologie des tumeurs, Faculté des sciences pharmaceutiques et biologiques de Paris, Université René Descartes Paris 5, 75006 Paris [V. D-M., S. R., D. B.]; Institut National de la Santé et de la Recherche Médicale, Cytokines et Immunologie des Tumeurs Humaines [M. E. B., H. E., G. D., J. T., I. V., J. M., S. C., F. M-C.], Département de Biologie Oncologique [D. B.], Institut Gustave Roussy, 94805 Villejuif; and Service d’Anatomie-Pathologie, Institut Mutualiste Montsouris [P. V.] and Laboratoire de Biochimie des Signaux Régulateurs Cellulaires et Moléculaires, Centre National de la Recherche Scientifique-Universite Pierre et Marie Curie [M. L.], 75014 Paris, France

We described previously a CTL clone able to lyse the autologous carcinoma cell line IGR-Heu after specific recognition of an HLA-A2/mutated -actinin-4 peptide complex. Here, we used IGR-Heu, cultured either as standard two-dimensional monolayers or as three-dimensional spheroids, to further analyze the influence of target architecture on CTL reactivity. Interestingly, we found that changes in the tumor structure from two- to three-dimensional induced a dramatic decrease in its capacity to activate autologous CTL, as measured by IFN- and tumor necrosis factor- secretion. These functional alterations were attributable neither to MHC class I expression nor to tumor antigen (Ag) down-regulation, because IGR-Heu, cultured as two- or three-dimensional, expressed similar levels of HLA-A2 and -actinin-4. More importantly, incubation of three-dimensional cells with synthetic epitope completely restored cytokine release by CTL. This defective Ag presentation correlated with a decrease in heat shock protein (hsp)70 expression by three-dimensional tumors compared with two-dimensional cells. Furthermore, transfection of the tumor cells with hsp70 cDNA completely restored the Ag-presenting potential of spheroids and, therefore, cytokine production by T cells. These data strongly suggest that hsp70 down-regulation in three-dimensional cells may result in tumor resistance to the immune response.

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