Irradiated CIITA-positive mammary adenocarcinoma cells act as a potent anti-tumor-preventive vaccine by inducing tumor-specific CD4+ T cell priming and CD8+ T cell effector functions

Abstract

In the present study, we investigated the possibility to use irradiated, non-replicating class II transcriptional activator (CIITA)-transfected tumor TS/A cells as a cell-based vaccine. Eighty-three percent of TS/A-CIITA-vaccinated mice were completely protected from tumor growth and the remaining 17% displayed significant reduction of tumor growth. In contrast, only 30% of mice injected with irradiated TS/A parental cells were protected from tumor growth, whereas the remaining 70% of animals remained unprotected. Immunity generated in the TS/A-CIITA-vaccinated mice correlated with an efficient priming of CD4(+) T cells and consequent triggering and maintenance of CD8(+) CTL effectors, as assessed by adoptive transfer assays. Important qualitative differences were observed between the two cell-based vaccines, as TS/A-CIITA-vaccinated mice developed a CTL response containing a large proportion of anti-gp70 AH1 epitope-specific cells, completely absent in TS/A-vaccinated mice, and a mixed T(h)1/T(h)2 type of response as opposed to a T(h)2 type of response in TS/A-vaccinated mice. Finally, in TS/A-CIITA-vaccinated mice, a statistically significant reduction in the percentage and absolute number of CD4(+) CD25(+) T regulatory cells as compared with those of untreated mice with growing tumors (P < 0.001) or mice vaccinated with TS/A parental cells were observed. These results let to envisage the use of CIITA-transfected non-replicating tumor cells as a vaccination strategy for prevention and, possibly, adjuvant immunotherapy in human settings.

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

“…[11][12][13][14] In this study, we extended this observation to tumor cells of the H-2 b genetic background, which at variance with H-2 d genotype can express only one of the two MHC-II molecules, the IA but not the IE molecule. Two distinct MHC-II-negative tumor cell lines, the MC38 colon carcinoma and the LLC Lewis lung carcinoma, highly tumorigenic in vivo, became strongly immunogenic after de novo expression of MHC-II molecules mediated by CIITA transfection.…”

“…In tumor cells of the H-2 d genetic background, expressing both IA and IE molecules, this approach has proven to be particularly successful since we could demonstrate that highly tumorigenic cells of both epithelial and connective tissue origin (carcinomas and sarcomas), rendered MHC-II-positive upon CIITA transfection, not only could be rejected or strongly delayed in their growth when injected in syngeneic immunocompetent recipients (Balb/C mice), but also could stimulate an anamnestic response capable to induce rejection of parental untransfected, MHC-II-negative cells. [11][12][13][14] Importantly, protective immunity could be transferred to na€ ıve syngeneic Balb/C mice by injecting CD4 C TH cells from mice "vaccinated" with CIITA-transfected tumor cells. 13,14 All together, our previous results indicated that MHC-II molecules expressed in tumor cells were necessary to induce a potent adaptive immune response against the tumor in vivo, that this response was mastered by CD4…”

“…[11][12][13][14] Importantly, protective immunity could be transferred to na€ ıve syngeneic Balb/C mice by injecting CD4 C TH cells from mice "vaccinated" with CIITA-transfected tumor cells. 13,14 All together, our previous results indicated that MHC-II molecules expressed in tumor cells were necessary to induce a potent adaptive immune response against the tumor in vivo, that this response was mastered by CD4…”

Introduction of theCIITAgene into tumor cells produces exosomes with enhanced anti-tumor effects

“…Our study was distinguished from several studies reported by others that used tumor cells modified with CIITA gene as cancer vaccine (Armstrong et al, 1997;Mortara et al, 2009). By using exosomes, we could expect fewer side effects than when tumor cells themselves were used.…”

Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy

“…At some point in their natural history, most tumors are able to present antigens and act as antigen-presenting cells (APCs) 17 . However, the lack of co-stimulatory molecules on tumor cells promote tolerance, thus exerting detrimental effects.…”