CD4(+) T cells in adoptive immunotherapy and the indirect mechanism of tumor rejection

Tumor-specific CD4(+) effector T cells often play a decisive role in immuno logic tumor rejection, in some cases without evident co-participation of CD 8(+) T cells. During such CD4(+) T-cell-mediated rejection there is often n o detectable direct contact between T cells and tumor cells. Optimally prep ared, adoptively transferred CD4(+) T cells can reject established tumors w ith great efficiency even when targeted tumor cells express no MHC Class II molecules, implying that recognition of tumor antigen (Ag) occurs via MHC: Class II-expressing host antigen-presenting cells (APC) within the tumor. Because consequent rejection also excludes Ag-specific contact between CD4( +) T cells and MHC Class IIneg tumor cells, the most critical CD4(+) T-cell -mediated event is likely cytokine release, resulting in an accumulation an d activation of accessory cells such as tumoricidal macrophages and lymphok ine-activated killer cells. Although such. an indirect rejection mechanism may appear antithetical to popular strategies centered on CD8(+) cytotoxic T cells (CTL), current evidence suggests that even CD8(+) T-cell-mediated r ecognition/rejection often bypasses direct tumor cell contact and is largel y cytokine mediated. While CTL are likely to participate prominently in man y models of tumor rejection, indirect mechanisms of recognition/ rejection have the theoretical advantage of remaining operative even when individual tumor cells evade direct contact by down-regulating MHC and/or Ag expressio n.