The aim of the present study was to determine whether the combination of two modalities of immunotherapy, targeting two different tumor antigens, may be feasible and non-toxic, yet enhance the killing of a human breast cancer cell line. The first modality was tumor growth factor α-Pseudomonas exotoxin 38 (TGFα-PE38), which specifically targets and kills tumor cells that express the epidermal growth factor receptor. The second modality was mucin-1 (MUC1)-specific cytotoxic T lymphocytes (CTLs), generated by MUC1 stimulation of peripheral blood mononuclear cells, to target the human breast cancer cell line, MCF7. TGFα-PE38 exhibited specific lysis of the MCF7 cells in a concentration- and time-dependent manner. TGFα-PE38 did not kill the normal hematopoietic stem cells or CTLs. Furthermore, TGFα-PE38 was not inhibitory for the growth or differentiation of the normal human hematopoietic stem cells into erythroid and myeloid colonies. In addition, TGFα-PE38 did not inhibit the killing function of CTLs, either when preincubated or co-incubated with CTLs. Finally, therapeutic enhancement was observed, in that TGFα-PE38 and CTLs were additive in the specific lysis of the MCF7 cells. These two modalities of immunotherapy may be beneficial for humans with breast cancer with or without other therapies, including autologous hematopoietic stem cell transplantation, specifically for purging cancer cells from hematopoietic stem cells prior to transplantation.
Abstract. CpG-ODNs activate various immune cell subsets and induce the production of numerous cytokines. To determine whether a CpG-ODN-activated innate immune system, without the adaptive immune system, was capable of protecting against cancer cell growth, NOD/SCID mice, which do not have T or B cell function but have a functional innate immune system, were used as a model system. NOD/SCID mice were injected subcutaneously with human prostate cancer cells followed by subcutaneous injection of incremental doses of CpG-ODNs. CpG-ODNs displayed a dose-related antitumoral effect leading to the prevention of tumor growth. These results indicate that ODNs are capable of activating the innate immune system and destroying human cancer cells in the absence of the adaptive immune system. IntroductionOne modality for the killing of cancer cells is immunotherapy. Oligodeoxynucleotides with unmethylated deoxycytidyldeoxyguanosine dinucleotides (CpG-ODN) stimulate immunity. CpG-ODNs are recognized by the toll like receptor-9 (TLR9) and mimic the immunostimulatory route of bacterial DNA. Certain synthetic ODNs contain an unmethylated CpG dinucleotide and, when injected into mice, activate various immune cell subsets, including macrophages, (1,2) dendritic cells (DCs) (3) and natural killer (NK) cells (1,2), inducing the production of a wide variety of cytokines (2,4,5). CpG motifs flanked by two 5' purines and two 3' pyrimidines appear to be the most potent immunostimulatory sequences (1). ODNs containing such immunostimulatory CpG motifs are promising immune adjuvants (5,6).Immunodeficient mice, such as non-obese, diabetic, severe combined immunodeficient (NOD-SCID) mice, have been used to study the growth of tumor cells (7), since they do not reject human tumors due to the lack of T and B cells (6). SCID mice models of cancer mimic human disease. Generally, tumor cells xenografted into SCID mice preserve their original histological and biological characteristics (8,9). In addition, NOD-SCID mice retain macrophage, dendritic cell (DC), NK cell and complement activity (10). These innate immune cells may be stimulated with CpG-ODN to attempt to prevent human tumor development in these mice. In vitro tumor cell lytic activity induced by CpG-ODN has been shown to be limited to NK cells (11). In vivo tumor rejection in immune competent mice induced by CpG-ODN was dependent upon the NK cell population (12,2).In other studies, CpG-ODN treatment has been proven to reduce the size of tumors in immunocompetent mice (2,4,5) and nude mice, which lack CD4 and CD8 lymphocytes (2). In addition, there are also ongoing trials in humans (www.clinicaltrials.gov). To further assess the mechanism of CpG-ODN protection against cancer growth, we studied whether CpG-ODN activation of the innate immune system, without the adaptive immune system, protects against cancer growth in NOD-SCID mice, which do not have functional T or B cells, but have macrophages, DCs, complements and NK cells, which if activated, elicit an immune response. Materials and ...
Interaction between antigen presenting cells and T lymphocytes, through receptors and co-stimulatory molecules present on the surface of these cells, is one of the key means to modulate the adaptive immune system. Tucaresol, a Schiff-base-forming chemical, can be used as a substitute for the physiological donor of carbonyl groups of antigen presenting cells, which can interact with the amine groups of T lymphocytes to modulate the adaptive immune system. This study was done to determine whether tucaresol can enhance killing of cancer cells in vitro as well as protect non-obese diabetic severe combined immunodeficient mice from tumor development by mucin 1 stimulated human mononuclear cells through the adaptive immune system. The expected hypothesis was not supported. Percent specific lysis of MCF-7 tumor cells by mucin 1 stimulated human mononuclear cells was reduced by tucaresol. Furthermore, tucaresol abolished the protective effect of mucin 1 stimulated human mononuclear cells against MCF-7 breast cancer cell growth in non-obese diabetic severe combined immunodeficient mice. This study implies that tucaresol may be of use as an immunosuppressive agent.
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