ABSTRACT
While a high frequency of Th1 cells in tumors is associated with improved cancer prognosis, this benefit has been attributed mainly to support of cytotoxic activity of CD8+ T cells. By attempting to potentiate antibody-driven immunity, we found a remarkable synergy between CD4+ T cells and tumor-binding antibodies. This surprising synergy was mediated by a small subset of tumor-infiltrating CD4+ T cells that express the high-affinity Fcγ receptor for IgG (FcγRI) in both mouse and human patients. These cells efficiently lyse tumor cells coated with antibodies through concomitant crosslinking of their T cell receptor (TCR) and FcγRI. By expressing FcγRI and its signaling chain in conventional CD4+ T cells, we successfully employed this mechanism to treat established solid cancers. Overall, this discovery sheds new light on the biology of this T cell subset, their function during tumor immunity, and the means to utilize their unique killing signals in immunotherapy.
Subject(s)
Antibody-Dependent Cell Cytotoxicity/immunology , Receptors, IgG/metabolism , Th1 Cells/classification , Th1 Cells/immunology , Animals , CD4-Positive T-Lymphocytes/classification , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Female , HEK293 Cells , Humans , Immunotherapy, Adoptive , Male , Mammary Neoplasms, Experimental/immunology , Mammary Neoplasms, Experimental/therapy , Melanoma, Experimental/immunology , Melanoma, Experimental/therapy , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , T-Lymphocyte Subsets/immunologyABSTRACT
Dendritic cells (DC) are heterogeneous cell populations that differ in their cell membrane markers, migration patterns and distribution, and in their antigen presentation and T cell activation capacities. Since most vaccinations of experimental tumor models require millions of DC, they are widely isolated from the bone marrow or spleen. However, these DC significantly differ from blood and tumor DC in their responses to immune complexes (IC), and presumably to other Syk-coupled lectin receptors. Importantly, given the sensitivity of DC to danger-associated molecules, the presence of endotoxins or antibodies that crosslink activation receptors in one of the isolating steps could result in the priming of DC and thus affect the parameters, or at least the dosage, required to activate them. Therefore, here we describe a detailed protocol for isolating MoDC from blood and tumors while avoiding their premature activation. In addition, a protocol is provided for MoDC activation with tumor IC, and their subsequent analyses.
Subject(s)
Antigen-Antibody Complex/metabolism , Dendritic Cells/immunology , Monocytes/metabolism , Neoplasms/immunology , Animals , Humans , MiceABSTRACT
Polyethylene glycol is a ubiquitous, water-soluble, organic compound found in a wide variety of commercially available products. While generally a benign substance, in rare instances, it can induce hypersensitivity reactions. Herein, we describe a case of anaphylaxis to polyethylene glycol-containing lubricating gel used for a transvaginal ultrasound. This case highlights the importance of early recognition of a rare cause of anaphylaxis that may occur in the health-care setting. It is of particular importance given the widespread use of similar lubricating materials in multiple practice settings for the use of internal examinations and ultrasonography.