CD40 ligand promotes priming of fully potent antitumor CD4(+) T cells in draining lymph nodes in the presence of apoptotic tumor cells

The presence or absence of CD4(+) T cell help can determine the direction o f adaptive immune responses toward either cross-priming or cross-tolerance. It has been demonstrated that interactions of CD40-CD40 ligand can replace CD4(+) T cell help and enable dendritic cells to prime cytotoxic T cells. Here, we demonstrate that antitumor reactivity induced in regional lymph no des (LNs) by s.c. injection of CD40 ligand (CD40L)-transduced tumor (MCA205 CD40L) showed far superior therapeutic efficacy against established brain tumors of a weakly immunogenic fibrosarcoma, MCA205, when adoptively transf erred. Coinjection of apoptotic, but not necrotic parental tumor cells with CD40L-expressing tumor cells caused a strong synergistic induction of anti tumor reactivity in tumor-draining LNs. Freshly isolated T cells from LNs i mmunized with apoptotic parental tumor cells and MCA205 CD40L were capable of mediating regression of the parental tumor in vivo. In contrast, T cells derived from LNs immunized without MCA205 CD40L required ex vivo anti-CD3/ IL-2 activation to elicit therapeutic activity. On anti-CD3/IL-2 activation , cells from LNs, immunized with MCA205 CD40L exhibited superior per cell a ntitumor reactivity. An in vitro depletion study revealed that either CD4() or CD8(+) T cells could mediate therapeutic efficacy but that the antitum or efficacy mediated by CD4(+) T cells was far superior. Cytosolic flow cyt ometric analyses indicated that priming of CD4(+) cells in LNs draining CD4 0L-expressing tumors was polarized to the Th1 type. This is the first repor t that fully potent antitumor CD4(+) T cell priming was promoted by s.c. in jection of CD40L-transduced tumor in the presence of apoptotic tumor cells.