Here we demonstrate that the murine mammary adenocarcinoma cell line TS/A, a highly malignant MHC-II-negative tumor, is rejected in vivo if genetically engineered to express MHC-II molecules by transfer of the MHC-II transactivator CIITA. TS/ACIITA cells are fully rejected by 93% of the syngeneic recipients and have a significantly lower growth rate in the remaining 7% of animals. Rejection requires CD4+ and CD8+ cells, but not B cells or NK cells. in vivo depletion experiments showed that CD4+ T cells are fundamental in the priming phase, whereas CTLs are the major anti-tumor effectors. All tumor rejecting animals are protected against rechallenge with the parental TS/A tumor. CTLs specific for a peptide of the envelope gp70 of an endogenous ecotropic retrovirus were identified and explained the specificity of the newly acquired effector mechanism of rejection against the TS/ A. Immunohistochemical analysis showed a dramatic subversion of the tumor microenvironment in TS/A-CIITA-injected as compared to parental TS/A-injected mice. At day 5 post-inoculation a higher infiltrate of CD4+ T cells in mice bearing TS/A-CIITA was observed. Subsequently, from day 7 through day 10, TS/A-CIITA tumors showed higher number of both CD4+ and CD8+ cells, dendritic cells, and neutrophils together with massive necrosis. The frequency of IFN-g-secreting splenocytes early after inoculations was also assessed by an ex vivo ELISPOT assay. Only rejecting TS/A-CIITA animals showed a high frequency of IFN-g-secreting cells. Importantly, CD4 and CD8 depletion experiments revealed that at the time of tumor resolution the major cell population recognizing the TS/A-CIITA cells was of CD4 origin. This is the first example of successful tumor vaccination by genetic transfer of CIITA. These results open the way to a possible use of CIITA for increasing both the inducing and the effector phase of the anti-tumor response.

A new strategy of tumor vaccination based on mammary adenocarcinoma cells transduced with the MHC class II transactivator CIITA

MORTARA, LORENZO;TOSI, GIOVANNA;DE LERMA BARBARO, ANDREA;ACCOLLA, ROBERTO
2005-01-01

Abstract

Here we demonstrate that the murine mammary adenocarcinoma cell line TS/A, a highly malignant MHC-II-negative tumor, is rejected in vivo if genetically engineered to express MHC-II molecules by transfer of the MHC-II transactivator CIITA. TS/ACIITA cells are fully rejected by 93% of the syngeneic recipients and have a significantly lower growth rate in the remaining 7% of animals. Rejection requires CD4+ and CD8+ cells, but not B cells or NK cells. in vivo depletion experiments showed that CD4+ T cells are fundamental in the priming phase, whereas CTLs are the major anti-tumor effectors. All tumor rejecting animals are protected against rechallenge with the parental TS/A tumor. CTLs specific for a peptide of the envelope gp70 of an endogenous ecotropic retrovirus were identified and explained the specificity of the newly acquired effector mechanism of rejection against the TS/ A. Immunohistochemical analysis showed a dramatic subversion of the tumor microenvironment in TS/A-CIITA-injected as compared to parental TS/A-injected mice. At day 5 post-inoculation a higher infiltrate of CD4+ T cells in mice bearing TS/A-CIITA was observed. Subsequently, from day 7 through day 10, TS/A-CIITA tumors showed higher number of both CD4+ and CD8+ cells, dendritic cells, and neutrophils together with massive necrosis. The frequency of IFN-g-secreting splenocytes early after inoculations was also assessed by an ex vivo ELISPOT assay. Only rejecting TS/A-CIITA animals showed a high frequency of IFN-g-secreting cells. Importantly, CD4 and CD8 depletion experiments revealed that at the time of tumor resolution the major cell population recognizing the TS/A-CIITA cells was of CD4 origin. This is the first example of successful tumor vaccination by genetic transfer of CIITA. These results open the way to a possible use of CIITA for increasing both the inducing and the effector phase of the anti-tumor response.
2005
Mortara, Lorenzo; Castellani, P.; Meazza, R.; Tosi, Giovanna; DE LERMA BARBARO, Andrea; Procopio, F.; Zardi, L.; Ferrini, S.; Accolla, Roberto...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/1776717
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