Eliciting cytotoxic T lymphocytes against acute myeloid leukemia-derived antigens: evaluation of dendritic cell-leukemia cell hybrids and other antigen-loading strategies for dendritic cell-based vaccination

Abstract

Dendritic cells (DC) have been successfully used in clinical pilot studies to induce tumor-specific immunity as well as clinical response in selected patients. However, DC-based immunotherapy remains a challenge and several parameters need to be examined in order to optimize the induction of anti-tumor immune responses. This study focuses on DC vaccination for leukemia and evaluates the in vitro efficacy of three different strategies for generating antigen-loaded DC-based vaccines for the induction of major histocompatibility complex (MHC) class I-restricted anti-leukemia cytotoxic T lymphocyte (CTL) responses. These included direct fusion of DC with leukemia cells to generate DC-leukemia cell hybrids, and DC pulsed with either apoptotic leukemia cell fragments or whole tumor cell lysates. Using either the U937 cell line or primary human acute myeloid leukemia blasts (AML), DC-leukemia cell hybrids were found to be the most potent in vitro inducers of CTL activity. DC pulsed with apoptotic tumor cell fragments were less efficient, but induced a more potent CTL response compared to tumor lysate-pulsed DC. The CTL responses were both MHC class I-restricted and antigen-specific, as shown by the inability of the CTL to lyse other control targets. The data presented here suggest that the method of antigen loading onto DC may be critical in the design of tumor vaccines.

<i>In vitro</i> analysis of T cell responses induced by breast tumor cell lysate pulsed with autologous dendritic cells

“…Among them whole tumor cells carry all the potential known and unknown tumor associated antigens (TAAs) that will be processed and presented on DC surface result in a polyclonal expansion of both CD4 + and CD8 + T cells [22], another advantages of using whole tumor cells as antigen is that unlike peptide antigens they can be used for patients with any HLA types. Furthermore, regardless of antigen types used in pulsing DCs, in the most cases this method of tumor antigen presentation could elicit tumor specific T cell responses in vitro [16][17][18][19][20][21].…”

“…The previous studies have shown that multiple tumor antigens do exist which can be used to induce autologous tumor specific T cell responses in vitro, therefore an alternative strategy for effective vaccination may be the use of unfractionated tumor derived antigens such as tumor cell lysate [16], peptides eluted from tumor cell membrane [17], apoptotic tumor cell [18] tumor peptide pulsed DC derived exosomes [19] fusion of tumor and dendritic cells [20] and tumor cell RNA [21]. Among them whole tumor cells carry all the potential known and unknown tumor associated antigens (TAAs) that will be processed and presented on DC surface result in a polyclonal expansion of both CD4 + and CD8 + T cells [22], another advantages of using whole tumor cells as antigen is that unlike peptide antigens they can be used for patients with any HLA types.…”

Generation and functional assessment of antigen-specific T cells stimulated by fusions of dendritic cells and allogeneic breast cancer cells

“…In this case, the tumor antigens, known or unidentified, can be fully presented in the context of self HLA class I and class II molecules to autologous T cells. Allogeneic DC have been used to fuse with syngeneic or autologous tumor cells [3,[6][7][8]. The advantage of this approach is that the fusion cells express both tumor-derived HLA class I molecules for the presentation of self MHC-restricted tumor peptide and allogeneic HLA class II molecules derived from the DC for direct stimulation of patient CD4 T cells [9].…”

Antibody opsonization of tumor cell membranes using hapten-PEG-lipid conjugates

“…This body to search rin, which form n activates the fective preparat h as transfect ake of tumor-an mature DCs w 5,16] . [7] , antigen-IgG s [12][13][14] , or the u urces, WTCs m necessitate hu ave some pos sulting in inter t "vaccination o anoma-specific lyclonal T cell ns of using sin ell epitopes [11] ng and Informat ivo. There are s en DNA or m mplexes [8][9][10] or Cs by immatur l because they e antigen analy unknown num riginal immuni s is safe (elicit nity" [3] .…”