Monoclonal Antibodies Targeted Against Melanoma and Ovarian Tumors Enhance Dendritic Cell-Mediated Cross-Presentation of Tumor-Associated Antigens and Efficiently Cross-Prime CD8+ T Cells

Abstract

Dendritic cells (DCs) constitute very attractive vectors for cancer immunotherapy due to their ability to efficiently capture and present tumor antigens, which initiates tumor-directed T-cell responses. Because the initiation of cytotoxic anti-tumor immune responses requires the cross-presentation mechanism, antigen targeting to DCs represents a very important step in the chain of events that constitutes the cross-priming immune process. In the current study, we explored the ability of DCs loaded with antibody-coated melanoma and ovarian carcinoma tumor cells to cross-present tumor antigens to CD8+ T cells and elicit in vitro anti-tumor immune responses. Coating melanoma and ovarian cancer cells with monoclonal antibodies against different surface antigens (CD44, ME491, LFA-3, and CD24) expressed by the tumor cells promoted the cross-presentation of the tumor-associated antigens as MART-1, gp100, tyrosinase, and NY-ESO-1 by DCs to CD8+ T. These tumor antigen-specific CD8+ T-cell populations resulting from the DC-mediated cross-priming process were identified using specific immune tetramers and were a few fold larger than the ones generated using peptide-pulsed or apoptotic tumor cell-loaded DCs. The CD8+ T cells generated by DCs loaded with monoclonal antibody-coated tumor cells were cytotoxic against the primary melanoma and ovarian carcinoma cells. Thus, targeting monoclonal antibody-coated tumor cells to DCs is a novel method that opens new perspectives for immunotherapy strategies.

Selection of Immunostimulant AS15 for Active Immunization With MAGE-A3 Protein: Results of a Randomized Phase II Study of the European Organisation for Research and Treatment of Cancer Melanoma Group in Metastatic Melanoma

“…Despite the absence of the MAGE protein at the cell surface, antibodies could play an active role through cross-presentation and subsequent T-cell activation. 34,35 No difference in isotype switching was observed between the two treatment arms (data not shown). Here, with one exception, no patients had anti-MAGE-A3 antibodies at baseline, a finding reported as rare by others, 14,23 in contrast to patients with resected lung cancer, where 7% of patients were seropositive at baseline.…”

CTL induction by cross‐priming is restricted to immunodominant epitopes

“…Similarly, CD4 1 T-cell help or stimulation by anti-CD40 antibody resulted in maturation of pAPC and enhanced cross-priming [16,17]. In addition, antigen-antibody complexes that target antigen to Fc g receptor-expressing DC efficiently induce CTL responses by cross-priming [10,18,19]. Cross-priming and direct priming are redundant mechanisms for the induction of tumor-specific T-cell immunity [20].…”

“…In addition, antigen-antibody complexes that target antigen to Fc g receptor-expressing DC efficiently induce CTL responses by cross-priming [10,18,19]. Cross-priming and direct priming are redundant mechanisms for the induction of tumor-specific T-cell immunity [20].…”

Monoclonal antibodies for the treatment of cancer

“…Numerous pre-clinical studies support the claim that tumor targeted antibodies can elicit adaptive immune responses, and a growing pool of clinical evidence suggests that this mechanism may contribute to the clinical efficacy of antibodies. DCs loaded with antibody coated ovarian and melanoma cells were able to elicit tumor specific CTLs [37]. Moreover, these CTLs were capable of killing the primary ovarian and melanoma cells [37].…”

“…DCs loaded with antibody coated ovarian and melanoma cells were able to elicit tumor specific CTLs [37]. Moreover, these CTLs were capable of killing the primary ovarian and melanoma cells [37]. Human DC loaded with myeloma cells coated with anti-syndecan-1 antibodies were able to generate CTLs specific for cancer-testis antigens expressed by the tumor cells [36].…”