Immunotherapy of murine B-cell lymphoma mediated by agonistic anti-CD40 antibody : role of co-stimulation in generation of CD8+ CTL

Abstract

Agonistic monoclonal antibodies directed against murine CD40 can be used in experimental settings to induce anti-lymphoma T-cells that are able to affect primary tumour eradication in vivo. These anti-tumour CTL provide both protection against re-challenge with the original vaccinating tumour line and, furthermore, prevent relapse, thereby affecting long-term survival. Such therapeutic strategies are desirable in order to provide durable responses against human lymphomas without evolving adverse side-effects.

Here, we further investigate the mechanism by which anti-CD40 exerts its therapeutic activity and demonstrate that interactions via the TNFR family member 4-1BB contribute to the expansion of anti-tumour CTL and, hence, survival following immunotherapy of lymphoma; indeed, we show that all tumour-specific CTL generated during anti-CD40-induced immunotherapy express this molecule. Furthermore, we demonstrate for the first time that the murine lymphomas used in these studies invoke an immunological response prior to anti-CD40 administration which is characterised by the phenotypic maturation of DCs and the differentiation of CD8^* T-cells, as well as the accumulation of these cells at the site of tumour. Importantly, the kinetics and magnitude of these responses are augmented by administration of anti-CD40 thereby suggesting that this mAb exerts its therapeutic activity by the boosting of a pre-existing ineffectual adaptive immune response.  Data shown here suggest that enhanced DC maturation following administration of anti-CD40 to tumour-bearing animals may contribute to this effect and, hence, support the hypothesis that anti-CD40 operates at the axis of the professional APC in order to affect the rejection of both CD40-positive and CD40-negative tumours.

In addition, we show that both CD8^* T-cell lines and immortalised hybridomas derived from tumour-reactive CD8^* CTL can be established in vitro from animals in remission following anti-CD40-induced immunotherapy. These techniques are new to this laboratory and provide a basis for the screening of a lymphoma-derived cDNA library in order to identify the tumour rejection antigens operating in this system.

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