Dendritic cells (DC) can achieve cross-presentation of naturally-occurring tumor-associated antigens after phagocytosis and processing of dying tumor cells. They have been used in different clinical settings to vaccinate cancer patients. We have previously used gamma-irradiated MART-1 expressing melanoma cells as a source of antigens to vaccinate melanoma patients by injecting irradiated cells with BCG and GM-CSF or to load immature DC and use them as a vaccine. Other clinical trials have used IFN-gamma activated macrophage killer cells (MAK) to treat cancer patients. However, the clinical use of MAK has been based on their direct tumoricidal activity rather than on their ability to act as antigen-presenting cells to stimulate an adaptive antitumor response. Thus, in the present work, we compared the fate of MART-1 after phagocytosis of gamma-irradiated cells by clinical grade DC or MAK as well as the ability of these cells to cross present MART-1 to CD8+ T cells. Using a high affinity antibody against MART-1, 2A9, which specifically stains melanoma tumors, melanoma cell lines and normal melanocytes, the expression level of MART-1 in melanoma cell lines could be related to their ability to stimulate IFN-gamma production by a MART-1 specific HLA-A*0201-restricted CD8+ T cell clone. Confocal microscopy with Alexa Fluor®647-labelled 2A9 also showed that MART-1 could be detected in tumor cells attached and/or fused to phagocytes and even inside these cells as early as 1 h and up to 24 h or 48 h after initiation of co-cultures between gamma-irradiated melanoma cells and MAK or DC, respectively. Interestingly, MART-1 was cross-presented to MART-1 specific T cells by both MAK and DC co-cultured with melanoma gamma-irradiated cells for different time-points. Thus, naturally occurring MART-1 melanoma antigen can be taken-up from dying melanoma cells into DC or MAK and both cell types can induce specific CD8+ T cell cross-presentation thereafter.

The surveillance of tumors by the immune system of cancer patients and its impact on disease progression and patient survival have been largely documented over the last years. In parallel, the use of therapeutic monoclonal antibodies (mAbs) in oncology has gained a widespread recognition as it has made it possible to increase patient survival and to ameliorate the quality of life in a number of cancers. However, the clinical responses observed following mAb treatment remain largely heterogeneous and their duration is still highly unpredictable. Recently, the concept that the injection of therapeutic antibodies not only triggers early anti-tumor events such as receptor blockade, cytostasis, apoptosis, complement-dependent cytotoxicity and/or antibody-dependent cytotoxicity but also allows the host immune system to fight tumor cells through the development of a long-lasting adaptive immunity has emerged. In the present review, we will examine the arguments that support this concept by detailing the cellular and molecular events likely to underlie the induction of an efficient anti-tumor adaptive immune response by mAbs. We will also discuss the consequences of this induction on the way therapeutic antibodies can be used and inserted in a more global immunotherapeutic approach aiming at strengthening the adaptive anti-tumor immune response developed by cancer patients.

Human IgG has only one conserved glycosylation site located in the Cγ2 domain of the Fc region that accounts for the presence of two sugar moieties per IgG. These IgG sugar cores play a critical role in a number of IgG effector functions. In the present review, we describe the main characteristics of IgG Fc glycosylation and some abnormalities of serum IgG glycosylation. We also discuss how glycosylation impacts on monoclonal antibodies (mAbs) and IVIg effector functions and how these molecules can be engineered. Several therapeutic antibodies have now been engineered to be no- or low-fucose antibodies and are currently tested in clinical trials. They exhibit an increased binding to activating FcγRIIIA and trigger a strong antibody-dependent cell cytotoxicity (ADCC) as compared to their highly-fucosylated counterparts. They represent a new generation of therapeutic antibodies that are likely to show a better clinical efficacy in patients, notably in cancer patients where cytotoxic antibodies are needed.

The anti-CD20 monoclonal antibody (mAb) rituximab has been used successfully for lymphoma therapy for more than 10 years. Although several direct mechanisms by which anti-CD20 mAbs act have been characterized in vitro, their specific role in clinical efficacy is still debated. Little is known about the possible antitumor immune response that they may induce in patients, despite clinical data suggesting a “vaccinal” effect. We show here that an initial treatment with anti-CD20 induces protection against human CD20-expressing tumor cells and allows immunocompetent mice to survive tumor challenge. This long-lasting protection requires the presence of the Fc portion of the anti-CD20 mAb and is achieved through the induction of a cellular immune response. Only CD4+ cells were needed at the beginning of the treatment, but both CD4+ and CD8+ cells were required after tumor challenge to achieve protection. Finally, we show that interleukin-2 treatment, given after tumor challenge, improves the overall survival rate, compared with that obtained by anti-CD20 treatment alone. These findings demonstrate that anti-CD20 mAbs exert therapeutic effects through the induction of an adaptive cellular immune response, aside from any direct mechanisms involving effectors from innate immunity.

Antibodies: better knowledge for a better use The therapeutic use of monoclonal antibodies is growing exponentially. Our knowledge on antibody structure, in particular that of IgG1, largely used in the clinic, has progressed remarkably. However, some formidable challenges still remain to be confronted, among which the increase of a yet-limited antibody efficacy, the lowering of the frequency of serious clinical adverse events, and the establishment of pre-clinical models that can be reliably extrapolated to humans represent major goals. The selection of relevant target antigens with regard to the pathology to be treated and to the expected effects of the antibody used is also a critical parameter. Facing these challenges, the amazing molecular plasticity of antibodies, as well as new antibody engineering approaches based on the most recent insights on the structure and biology of antibodies and their targets represent areas of research that will make monoclonal antibodies remarkable drugs for human health in a near future.

L’utilisation thérapeutique des anticorps monoclonaux connaît une croissance exponentielle. Nos connaissances sur leur structure, en particulier celle des IgG1 largement utilisées en thérapeutique, se sont considérablement accrues. Cependant, de nombreux défis demeurent : l’amélioration de l’efficacité de ces molécules qui reste limitée, la diminution des risques d’événements indésirables chez les patients, et la mise au point de modèles précliniques adéquats, extrapolables à l’être humain. La sélection de cibles pertinentes par rapport à la pathologie visée et aux effets induits par l’anticorps est également un paramètre critique. Face à tous ces défis, la remarquable plasticité moléculaire des anticorps ainsi que les nouvelles possibilités d’ingénierie fondées sur des connaissances accrues de la structure et de la biologie des anticorps et de leurs cibles constituent autant d’espaces de recherche pour faire des anticorps monoclonaux des médicaments exceptionnels pour la santé humaine dans les prochaines années.

Membrane Fcgamma receptors (FcgammaRs) can act either as potent activators of effector cell functions or as inhibitors of receptor-mediated cell activation following engagement by IgG antibodies bound to their target molecules. The remarkable ability of activating FcgammaRs to trigger antibody-dependent cellular cytotoxicity, cytokine release and phagocytosis/endocytosis followed by antigen presentation has stimulated the development of a number of therapeutic monoclonal antibodies whose Fc regions have been engineered to optimize their effector functions, mostly their killing activities. Conversely, the demonstration that inhibitory FcgammaRs can block or downmodulate effector functions has led to the concept that targeting these receptors is of interest in a number of pathologies. The use of bispecific antibodies leading to the crosslinking of FcgammaRIIB with activating receptors could induce immunomodulation in autoimmune or allergic diseases. Alternatively, the use of cytotoxic/antagonist anti-FcgammaRIIB antibodies could kill FcgammaRIIB-positive tumor cells or prevent the downmodulation of activating receptors. Thus, antibodies engineered to preferentially target activating or inhibitory FcgammaRs are currently being designed for therapeutic use.

Triethylene tetramine (TETA) is a novel ligand for G-quadruplex and has been reported to have many kinds of biological activities, including telomerase inhibition, inducing the senescence of tumor cells, etc. In this study, tumor inhibiting activity of TETA and its mechanism were investigated in HeLa cells, MCF-7 cells and mice transplanted with S180 tumor. Results indicated that TETA inhibited telomerase activity involved in decreasing the expression of human telomerase reverse transcriptase (hTERT). We also observed that a low concentration of TETA had limited ability to inhibit the growth of tumor cells in short-term culture, but it could significantly enhance antitumor activity of traditional antitumor drugs in vitro and in vivo.