Activation of Dendritic Cells That Cross-Present Tumor-Derived Antigen Licenses CD8+ CTL to Cause Tumor Eradication

Abstract

The fate of naive CD8+ T cells is determined by the environment in which they encounter MHC class I presented peptide Ags. The manner in which tumor Ags are presented is a longstanding matter of debate. Ag presentation might be mediated by tumor cells in tumor draining lymph nodes or via cross-presentation by professional APC. Either pathway is insufficient to elicit protective antitumor immunity. We now demonstrate using a syngeneic mouse tumor model, expressing an Ag derived from the early region 1A of human adenovirus type 5, that the inadequate nature of the antitumor CTL response is not due to direct Ag presentation by the tumor cells, but results from presentation of tumor-derived Ag by nonactivated CD11c+ APC. Although this event results in division of naive CTL in tumor draining lymph nodes, it does not establish a productive immune response. Treatment of tumor-bearing mice with dendritic cell-stimulating agonistic anti-CD40 mAb resulted in systemic efflux of CTL with robust effector function capable to eradicate established tumors. For efficacy of anti-CD40 treatment, CD40 ligation of host APC is required because adoptive transfer of CD40-proficient tumor-specific TCR transgenic CTL into CD40-deficient tumor-bearing mice did not lead to productive antitumor immunity after CD40 triggering in vivo. CpG and detoxified LPS (MPL) acted similarly as agonistic anti-CD40 mAb with respect to CD8+ CTL efflux and tumor eradication. Together these results indicate that dendritic cells, depending on their activation state, orchestrate the outcome of CTL-mediated immunity against tumors, leading either to an ineffective immune response or potent antitumor immunity.

In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

“…This finding is in line with other publications that report the existence of primed CD8 1 T cells in mice with progressing tumors. These T cells have been described as ''poised'' T cells, ready for action, not deleted or anergized, but also unfit to migrate or exert antitumoral effector functions [23,51]. Alternatively, multifaceted suppressive mechanisms could be restraining the effector functions of such potentially tumoricidal CD8 1 T cells [52].…”

“…processing tumor cells or tumor cell debris [23]. Based on this notion, it has been proposed that antigen cross-presentation by DC is a prerequisite for the efficacy of anti-CD137 treatment [3].…”

“…In vivo analysis of tumor Ag cross-presentation OVA-specific T-cell proliferation was assessed using CFSE-labeled OT-I T cells as described elsewhere [23]. Briefly, single-cell suspensions were prepared from the spleens of OT-I TCR transgenic mice.…”

“…It is still unresolved whether cross-presentation or direct presentation is the relevant mechanism governing tumor immunity [20,21]. Although some studies have suggested that the two processes act as redundant non-mutually exclusive mechanisms [22], other authors have proposed cross-presentation to be the major mechanism for the activation of naïve CD8 1 T cells [23].Experimentation in BM chimeric mice with differential expression of antigen-presenting molecules and in humans vaccinated with allogeneic tumor cells has demonstrated that the ability to cross-present cell-associated antigens is restricted to BM-derived APC [24,25]. Several groups have investigated the identity of the BM-derived APC involved in MHC class I-restricted presentation of exogenous antigens.…”

“…It is still unresolved whether cross-presentation or direct presentation is the relevant mechanism governing tumor immunity [20,21]. Although some studies have suggested that the two processes act as redundant non-mutually exclusive mechanisms [22], other authors have proposed cross-presentation to be the major mechanism for the activation of naïve CD8 1 T cells [23].…”