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The Cytotoxic T-Lymphocyte Response against a Poorly Immunogenic Mammary Adenocarcinoma Is Focused on a Single Immunodominant Class I Epitope Derived from the gp70 Env Product of an Endogenous Retrovirus¹

Department of Oncology and Surgical Sciences [A. R., S. D. S., A. Z., S. G., V. T., P. Z.], and Endocrine-Metabolic Laboratory, Internal Medicine, Department of Medical and Surgical Sciences [G. M., B. M.], University of Padova, Padova 35128; Cancer Immunotherapy and Gene Therapy Program, DIBIT, H. San Raffaele Scientific Institute, Milan 20132 [P. D.]; and Cancer Research Section, Department of Experimental Pathology, University of Bologna, Bologna 40126 [P-L. L., C. D. G.], Italy

The TS/A mouse mammary adenocarcinoma is a poorly immunogenic tumor widely used in preclinical models of cancer immunotherapy. CTLs have often been indicated as important in TS/A tumor destruction, but their generation in this model has been rarely studied, nor have their precise target(s) been identified. We hypothesized that the gp70 Env product of an endogenous murine leukemia virus could be a target antigen for TS/A-specific CTLs and investigated this possibility in four different TS/A cell lines engineered with the genes that encode IFN-, IFN-, interleukin-4, and B7.1, respectively. All tumor cell lines expressed gp70, albeit at different levels, as demonstrated by reverse transcription-PCR analysis. Transfected tumor cells exhibited a delayed growth in vivo, and partial tumor regression. Spleen cells from mice that displayed tumor regression had high percentages of CD8⁺ T cells that were specifically stained with L^d tetramers loaded with gp70_423–431, the antigenic epitope of gp70 protein. Mixed leukocyte-peptide and mixed leukocyte-tumor cultures, set up by stimulating splenocytes with the immunogenic peptide and with transfected TS/A tumor cells, respectively, resulted in similar large increases in tetramer-reactive CD8⁺ T cells and showed high lytic activity specific for gp70_423–431. Finally, in a Cold Target Inhibition assay, lytic activity of a mixed leukocyte-tumor culture was inhibited in an overlapping fashion by both the TS/A line used for restimulation and 293L^d cells loaded with gp70_423–431 peptide, but not by 293L^d cells pulsed with an irrelevant H-2 L^d epitope, thus demonstrating that all or most of the cytotoxic activity was directed exclusively against this antigenic epitope.

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