Is secretion of tumour-specific antigen important for cancer eradication by CD4(+) T cells?--Implications for cancer immunotherapy by adoptive T cell transfer

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.