The potential for cancer immunotherapy by adoptive transfer of CD4(+) T cells is 
gaining increased attention. Most cancer cells lack major histocompatibility 
complex (MHC) class II molecules and cannot present tumour-specific antigens 
(TSA) directly to CD4(+) T cells. We have reported that tumour-specific CD4(+) T 
cells collaborate with macrophages and dendritic cells. These professional 
antigen-presenting cells endocytose and process TSA to display antigenic 
peptides on their MHC class II molecules for indirect cancer cell recognition by 
CD4(+) T cells. We hypothesized that this critical step may depend on secretion 
of TSA by cancer cells. This was investigated in a mouse model for myeloma 
immunosurveillance mediated by CD4(+) T cells. From this study, several 
conclusions could be drawn. First, TSA secretion facilitates cancer 
immunosurveillance. Second, TSA secretion results in stronger activation of 
naïve tumour-specific CD4(+) T cells in lymph nodes. Third, TSA concentration 
within the tumour extracellular matrix must reach a certain threshold to allow 
successful cancer immunosurveillance. Fourth, treatment by local injection of 
purified TSA enhances immunity against cancer cells that do not secrete TSA. 
Fifth, secretion of TSA by at least some cancer cells within a tumour favours 
antitumour immunity. Therefore, we propose that CD4(+) T cells that recognize 
secreted TSA may be superior for immunotherapy by T cell transfer, because the 
local extracellular antigen concentration will be higher for secreted TSA. Thus, 
it is anticipated that secreted TSA will be more readily detected in vivo by 
transferred CD4(+) T cells, resulting in more efficient tumour eradication.