Cross-Priming of Naive Cd8 T Cells against Melanoma Antigens Using Dendritic Cells Loaded with Killed Allogeneic Melanoma Cells

Abstract

The goal of tumor immunotherapy is to elicit immune responses against autologous tumors. It would be highly desirable that such responses include multiple T cell clones against multiple tumor antigens. This could be obtained using the antigen presenting capacity of dendritic cells (DCs) and cross-priming. That is, one could load the DC with tumor lines of any human histocompatibility leukocyte antigen (HLA) type to elicit T cell responses against the autologous tumor. In this study, we show that human DCs derived from monocytes and loaded with killed melanoma cells prime naive CD45RA+CD27+CD8+ T cells against the four shared melanoma antigens: MAGE-3, gp100, tyrosinase, and MART-1. HLA-A201+ naive T cells primed by DCs loaded with HLA-A201− melanoma cells are able to kill several HLA-A201+ melanoma targets. Cytotoxic T lymphocyte priming towards melanoma antigens is also obtained with cells from metastatic melanoma patients. This demonstration of cross-priming against shared tumor antigens builds the basis for using allogeneic tumor cell lines to deliver tumor antigens to DCs for vaccination protocols.

Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma

“…In the present study we found that DCs phagocytosing apoptotic tumor cells elicit long-lived combined CD4 ϩ and CD8 ϩ immunity against the poorly immunogenic B16 melanoma. DCApo have been shown by Berard et al (22) to be able to prime naive human T cells in vitro to melanoma Ags. These findings together with our preclinical model set the stage for comparable studies in humans with DC-Apo as adjuvants for active immunization against cancer.…”

“…DCs are proving to be effective in initiating and expanding immune responses in humans (10,11), providing a rationale for their use as adjuvants for active immunization against melanoma (12)(13)(14)(15)(16). Different strategies have been developed to load DCs with tumor Ags, including MHC-restricted synthetic peptides derived from the Ag (12)(13)(14)(15)(16)(17), tumor RNA (18,19), tumor lysates (20), tumor-derived exosomes (21), and dying tumor cells (22)(23)(24)(25)(26); these have been assessed in preclinical models and, in some cases, clinical trials (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Tumor cells (dying cells or Ab-coated tumor cells) are of interest as an antigenic source, because the DCs would have the potential to present a broad range of tumor-associated Ags and on both MHC class I and II products regardless of the MHC haplotype of the patient (27)(28)(29)(30).…”

Potent Dendritic Cell Vaccine Loaded with Latent Membrane Protein 2A (LMP2A)

“…DCs loaded with protein can promote cellular immunity both in experimental animal models and humans (8)(9)(10)(11). Optimal antigen loading strategies provide epitopes presented by both MHC class I and class II leading to a diverse immune response in which many clones of cytotoxic T cells (CTLs) and CD4 + T cells are involved (12)(13)(14).…”

Long‐lasting cross‐presentation of tumor antigen in human DC

“…The molecular requirements for the cross-presentation of exogenous antigens by DC were also extensively analyzed in the last few years [27][28][29][30][31][32][33][34]. Because most studies analyzing cross-presentation in human DC used apoptotic cells or vesicles as the source of antigen [35,36], mechanistic analyses are not fully conclusive. Purified proteins or peptides, however, have also been used in a few studies that provided some insights into the mechanisms required for antigen delivery, processing and presentation by human DC [15,18,19,32,37,38].…”