MB49, an H2b+ murine bladder carcinoma cell line, naturally expresses the male-specific
minor histocompatibility antigen, HY, which can be used as a proxy tumour associated
antigen. The MB49 cell line, together with two HY-specific TCR-transgenic mouse strains
(as sources of tumour-specific CD4 and CD8 T cells), form a unique system in which anti-tumour
T cell responses can be manipulated and analysed. I have studied some basic but
critical immunological aspects of MB49 cells, adoptively transferred T cells and an
immunotherapeutic antibody.
I confirmed that MB49 cells express all three defined HY genes (Dby, Uty and
Smcy), and demonstrated that cultured and freshly isolated tumour cells display a distinct
phenotype. I found that MB49 tumours are very aggressive even though they are clearly
immunogenic. Female B6 mice are more efficient than males at controlling MB49 tumours,
especially when inoculated with a low tumour dose, suggesting that HY-specific T cell
responses make a significant contribution to immune control of MB49 tumours.
I evaluated three different immunotherapies for treating MB49 tumours: Whole
body irradiation followed by the adoptive transfer of Tumour Associated Antigen specific
CD4 T cells, or IL-15 expressing CD8 T cells, were found to inhibit the growth of MB49
tumours. Administration of anti-GITR mAbs was found to be very effective at eliminating
established MB49 tumours.
I observed a novel role for IL-2 in immunoregulation; by the suppression of the
differentiation of IL-17-producing Th17 cells.
Finally, I demonstrated that Transforming Growth Factor β is essential for the
tumour-induced expansion of natural regulatory T cells.
This study not only extends the current knowledge of the immunobiology of MB49
tumours but also lays a foundation for further investigation with respect to designing
rational T cell cancer immunotherapy using genetically manipulated, tumour-specific T
cells.