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Apoptosis-dependent Subversion of the T-Lymphocyte Epitope Hierarchy in Lymphoma Cells¹

Cancer Immunotherapy and Gene Therapy Program [P. C., A. M-F., V. T., M. B.], Unità di Spettrometria di Massa [F. M.], Università Vita Salute San Raffaele [C. R.], Istituto Scientifico H San Raffaele, Milan Italy, 20132; Dipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova, Padova, Italy, 35128 [G. M., A. R.]; and Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden, S-171 77 [J. M.]

Tumor cells undergoing programmed death are an attractive source of tumor-associated antigens, and evidences are available for their therapeutic efficacy in vivo when used either alone or in association with dendritic cells. However, little is known about the specificity of the immune response induced by such antigen formulation. Indeed, activation of specific proteases during apoptosis may influence the cytoplasmic degradation of proteins and the generation of CTL epitopes. We show here that on injection of C57BL/6 mice either with RMA lymphoma cells induced to apoptosis or bone marrow-derived dendritic cells pulsed with apoptotic RMA cells, a specific and protective CTL response is induced, which, however, is not directed against the immunodominant CTL epitope gag_85–93. Lack of in vivo expansion of gag_85–93-specific CTL in vaccinated mice is attributable to the apoptosis-dependent loss of gag_85–93 in dying tumor cells. Indeed, we found loss of gag_85–93 in RMA, MBL-2, and EL-4G+ lymphoma cells, which share gag_85–93 as an immunodominant CTL epitope, induced to apoptosis by UV irradiation, mitomycin C, doxorubicin, or daunorubicin. This phenomenon appears to be caspase-dependent, because caspase inhibition by N-benzyloxycarbonyl-Val-Ala-asp-fluoromethylketone prevents apoptosis of lymphoma cells and loss of gag_85–93. Therefore, subversion of the epitope hierarchy in apoptotic tumor cells might be relevant in the induction of tumor-specific T-lymphocyte responses.

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