CIITA-driven MHC-II positive tumor cells: Preventive vaccines and superior generators of antitumor CD4+ T lymphocytes for immunotherapy

Authors

  • Valeria Frangione,

    1. Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy
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    • PhD program in Experimental Medicine and Oncology, University of Insubria, Varese.

  • Lorenzo Mortara,

    1. Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy
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  • Patrizia Castellani,

    1. Laboratory of Cellular Biology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
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  • Andrea De Lerma Barbaro,

    1. Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy
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  • Roberto S. Accolla

    Corresponding author
    1. Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy
    • Department of Clinical and Biological Sciences, Faculty of Medicine and Surgery, University of Insubria, Via Ottorino Rossi, 9. 21100 Varese, Italy
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    • Fax: +39-332-217219


Abstract

In our study, we have investigated whether tumors of distinct histological origin can be rejected if expressing CIITA-driven MHC class II molecules. Moreover, we assessed whether antitumor lymphocytes generated by this approach could be used as an immunotherapeutic tool for established cancers. Stable CIITA-transfectants of C51colon adenocarcinoma, RENCA renal adenocarcinoma, WEHI-164 sarcoma as well as TS/A mammary adenocarcinoma were generated. Tumor cells transfectants were injected in vivo, and their growth kinetics and recipient's immune response were analyzed. Tumor rejection and/or retardation of growth was found for the first 3 CIITA-transfected tumor cell lines and confirmed for TS/A-CIITA. Animals rejecting CIITA-transfected tumors acquired specific immunological memory as demonstrated by resistance to challenge with parental tumors. Adoptive cell transfer experiments demonstrated that tumor immunity correlates with the efficient priming of CD4+ T helper cells and the consequent activation of CD8+ T lymphocytes. T cells from TS/A-vaccinated mice were used in an adoptive immunotherapy model of established tumors. The results showed the cure at early stages and significantly prolonged survival at later stages of tumor progression. Importantly, CD4+ T cells were clearly superior to CD8+ T cells in antitumor protective function. Interestingly, the protective phenotype was associated to both a Th1 and Th2 polarization of the immune effectors. These results establish the general application of our tumor vaccine model and disclose the additional application of this strategy for producing better lymphocyte effectors for adoptive antitumor immunotherapy.

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