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

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.