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Oncoimmunology. 2016 Nov 28;6(1):e1261777. doi: 10.1080/2162402X.2016.1261777. eCollection 2017.

CIITA-driven MHC class II expressing tumor cells can efficiently prime naive CD4+ TH cells in vivo and vaccinate the host against parental MHC-II-negative tumor cells.

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1
Department of Surgical and Morphological Sciences, School of Medicine, University of Insubria , Varese, Italy.

Abstract

Our previous studies showed that non-immunogenic H-2d tumor cells of distinct epithelial histotypes can become highly immunogenic, induce a protective CD4+ T cell response and vaccinate the animals against parental MHC-II-negative cells if they are rendered MHC class II-positive by stable transfection with the Air-1-encoded MHC-II transcriptional activator CIITA. These studies did not establish, however, whether tumor immunity was the consequence of a direct priming of naive CD4+ T lymphocytes by CIITA-driven MHC-II-expressing tumor cells or by MHC-II-tumor antigen complexes engulfed by dendritic cells (DC) and exposed on the surface of these professional antigen presenting cells (APC). In the present investigation, we provide definitive evidence that CIITA-tumor cells are the crucial APC in vivo for CD4+ T cell priming. By using a transgenic H-2b mouse model, the CD11c.DTR C57BL/6 mice, in which DC can be functionally deleted by administration of diphteria toxin, we show that CIITA-tumor cells of two distinct histotypes can be rejected or strongly retarded in their growth in DC-deleted mice. To rule out that in absence of DC, other professional APC could prime naive CD4+ T cells, we deleted the macrophages in CD11c.DTR C57BL/6 mice by administration of liposome Clodronate and still obtained rejection or strong retardation in tumor growth of CIITA-tumor cells. Our results challenge the diffuse belief that non-professional APC cannot efficiently prime naive T cells in vivo. Moreover, the demonstration of the general validity of our approach in different genetic backgrounds may open a way for new strategies of antitumor treatment in clinical settings.

KEYWORDS:

CD4+ T cells; CIITA; DC; MHC class II

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