CIITA-induced MHC class II expression in mammary adenocarcinoma leads to a Th1 polarization of the tumor microenvironment, tumor rejection, and specific antitumor memory.
OBJECTIVE
We have shown previously that the MHC class II-negative murine TS/A adenocarcinoma is rejected in vivo if induced to express MHC class II molecules by transfection of the MHC class II transactivator CIITA. In this study, we explored the immunologic basis of tumor rejection and the correlation between histopathology of tumor tissue and immune rejection.


METHODS
Stable TS/A-CIITA transfectants were generated and injected into mice. In vivo cell depletion, immunohistochemistry of tumor tissues, and immune functional assays were done to assess the cellular and immunologic basis of rejection.


RESULTS
Ninety-two percent of mice injected with TS/A-CIITA rejected the tumor and were completely resistant to challenge with parental TS/A. Only CD4+ and CD8+ cells were required for rejection. The tumor microenvironment in TS/A-CIITA-injected mice changed dramatically when compared with the TS/A parental-injected mice. Rapid infiltration with CD4+ T cells followed by dendritic cells, CD8+ T cells, and granulocytes was observed. Importantly, TS/A-CIITA cells could act as antigen-presenting cells because they process and present nominal antigens to CD4+ T cells. Tumor-specific CD4+ T cells of TS/A-CIITA-injected mice had the functional characteristics of Th1 cells and produced IFN-gamma and this was relevant for generation and maintenance of protective antitumor response, because IFN-gamma knockout mice were no longer rejecting TS/A-CIITA tumor cells.


CONCLUSIONS
CIITA-dependent MHC class II expression confers to TS/A tumor cells the capacity to act as a protective vaccine against the tumor by triggering tumor antigen presentation to T helper cells, antitumor polarization of cellular and soluble components of the tumor microenvironment, and establishment of antitumor immune memory.
Mortara
Lorenzo
L
Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy.
Castellani
Patrizia
P
Meazza
Raffaella
R
Tosi
Giovanna
G
De Lerma Barbaro
Andrea
A
Procopio
Francesco A
FA
Comes
Alberto
A
Zardi
Luciano
L
Ferrini
Silvano
S
Accolla
Roberto S
RS
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D018417:Th1 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019076:Transgenes
D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators