Genetically modified dendritic cells prime autoreactive T cells through a pathway independent of CD40L and interleukin 12: Implications for cancer vaccines

Genetic immunization through ex vivo transduction of dendritic cells has be en suggested as an effective approach to enhance antitumor immunity by acti vating both CD4(+) and CD8(+) T cells. Immunizing mice with dendritic cells transduced with an adenovirus expressing the human melanoma antigen glycop rotein 100 (DCAdhgp100) as a cancer vaccine, we demonstrated complete prote ctive immunity and a potent CTL response against melanomas expressing murin e glycoprotein 100 in a CD4(+) cell-dependent manner. Surprisingly, however , effective tumor rejection was not the result of cooperation between CD4() and CD8(+) T cells. Protective immunity was completely lost when CD4(+) c ells were depleted immediately before tumor challenge, whereas it was unaff ected by removal of CD8(+) cells, establishing a principal role for CD4(+) cells in the effector phase of tumor rejection. Neither protective immunity nor CTL generation in this model required interleukin 12, in spite of high levels of IFN-gamma secretion by tumor-reactive T cells. Most notably, the DCAdhgp100 vaccine could elicit protective antitumor CD4(+) cells in the a bsence of CD40 ligand, although it does not bypass the need for CD40-mediat ed signals to generate melanoma-reactive CTLs. Thus, in contrast to the cur rent thinking that the optimal cancer vaccine should include determinants f or both CD4(+) and CD8(+) cells, the potency of the DCAdhgp100 vaccine appe ars to be a result of its ability to directly prime autoreactive CD4(+) cel ls through a process that does not require interleukin 12 and CD40 signals.