CIITA-driven MHC class II expressing tumor cells can efficiently prime naive CD4⁺TH cellsin vivoand vaccinate the host against parental MHC-II-negative tumor cells

Abstract

Our previous studies showed that non-immunogenic H-2 d tumor cells of distinct epithelial histotypes can become highly immunogenic, induce a protective CD4 C 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 CD4C 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 CIITAtumor cells are the crucial APC in vivo for CD4C T cell priming. By using a transgenic H-2 b 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 CD4C 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.

CIITA-Transduced Glioblastoma Cells Uncover a Rich Repertoire of Clinically Relevant Tumor-Associated HLA-II Antigens

“…It has been reported before that CIITA-transfected tumor cells gained ability to prime in vivo naïve CD4+ cells, and thus, they may serve as APCs (19). We found 809, 1,017, and 1,048 application.…”

Tumor Immunology meets…Immunology: Modified cancer cells as professional APC for priming naïve tumor-specific CD4+ T cells

“…DTR mice, did not abrogate the capacity of these mice to reject or reduce the growth of MHC-II positive tumors. 39 Taken together, these observations unequivocally demonstrated the validity of our approach as a general strategy to increase the immunogenicity of tumor cells, to stimulate a strong and long lasting adaptive anti-tumor immunity and, importantly, to make a tumor cell an antigen presenting cell of its own TAAs for priming na€ ıve, tumor-specific TH cells (Fig. 1).…”

Biological Consequences of MHC-II Expression by Tumor Cells in Cancer

“…In the majority of studies, transduction of tumor cells with Ciita increased tumor rejection and led to resistance to challenge with parental cells in mouse models of breast cancer, sarcoma, lung cancer, and colon cancer (18,100,101,106,107). In a mouse model of breast cancer, Ciita þ clones with the highest surface expression of MHC-II were rejected at the highest rate (18), whereas depletion studies revealed that both CD4 þ and CD8 þ T cells, but not B cells or natural killer (NK) cells, were necessary for tumor rejection.…”