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LAG-3 Enables DNA Vaccination to Persistently Prevent Mammary Carcinogenesis in HER-2/neu Transgenic BALB/c Mice¹

Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy [P. C., C. C., E. Q., M. G., G. F.]; Center for Experimental Research and Medical Studies, S. Giovanni Battista Hospital, 10126 Turin, Italy [P. C., C. C., M. G., G. F.]; Laboratory of Tumor Immunology, Faculté de Pharmacie, 92296 Chatenay-Malabry, France [F. T.]; Department of Oncology and Neurosciences, "G. D’Annunzio" University, 66013 Chieti, Italy [M. I., E. D. C., P. M.]; Cancer Research Section, Department of Experimental Pathology, University of Bologna, 40126 Bologna, Italy [P-L. L.]; Molecular, Cellular and Animal Biology Department, University of Camerino, 62032 Camerino, Italy [A. A.]

Within 33 weeks of life, all 10 mammary glands of virgin BALB/c mice transgenic for the transforming rat HER-2/neu oncogene under the mammary tumor virus promoter (BALB-neuT mice) progress from atypical hyperplasia to invasive palpable carcinoma. Repeated DNA vaccination with plasmids coding for the extracellular and transmembrane domain of the protein product of rat HER-2/neu (r-p185^neu) delayed tumor onset and reduced tumor multiplicity, but this protection eventually declined, and few mice were tumor free at 1 year of age. Association of plasmid vaccination with administration of soluble mouse LAG-3 (lymphocyte activation gene-3/CD223) generated by fusing the extracellular domain of murine LAG-3 to a murine IgG2a Fc portion (mLAG-3Ig) elicited a stronger and sustained protection that kept 70% of 1-year-old mice tumor free. Moreover, this combined vaccination, which was performed when multiple in situ carcinomas were already evident, extended disease-free survival and reduced carcinoma multiplicity. Inhibition of carcinogenesis was associated with markedly reduced epithelial cell proliferation and r-p185^neu expression, whereas the few remaining hyperplastic foci were heavily infiltrated by reactive leukocytes. A stronger and enduring r-p185^neu-specific cytotoxicity, a sustained release of IFN- and interleukin 4, and a marked expansion of both CD8⁺/CD11b⁺/CD28⁺ effector and CD8⁺/CD11b⁺/CD28^- memory effector T-cell populations were induced in immunized mice. This combined vaccination also elicited a quicker and higher antibody response to r-p185^neu, as well as an early antibody isotype switch. These data suggest that the appropriate costimulation provided by mLAG-3Ig enables DNA vaccination to establish an effective protection, probably by enhancing cross-presentation of the DNA coded antigen.

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