ABSTRACT
The DNA damage response (DDR) alerts the immune system to the danger posed by DNA damage through the induction of damage-associated molecular pattern molecules, chemokines, and ligands for activating immune receptors such as lymphocyte function-associated antigen 1 (LFA-1), NKG2D, and DNAX accessory molecule 1 (DNAM-1). Here we provide evidence that OVA(257-264) -pulsed fibroblasts gain the ability to activate naïve OT-I CD8(+) T cells in response to DNA damage. The ability of fibroblasts to activate OT-I CD8(+) T cells depended on the upregulation of ICAM-1 on fibroblasts and DNAM-1 expression of CD8(+) T cells. OVA(257-264) -pulsed fibroblasts were able to induce a protective T-cell response against B16-OVA cells in a DDR-dependent manner. Hence, the DDR may alert the immune system to the presence of potentially dangerous cells by upregulating the expression of ligands that can induce the activation of innate and adaptive immune cells.
Subject(s)
Antigen-Presenting Cells/immunology , CD8-Positive T-Lymphocytes/immunology , DNA Damage/immunology , Fibroblasts/immunology , Animals , Antigen-Presenting Cells/metabolism , Antigens, Differentiation, T-Lymphocyte/immunology , Antigens, Differentiation, T-Lymphocyte/metabolism , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Ataxia Telangiectasia Mutated Proteins/immunology , Ataxia Telangiectasia Mutated Proteins/metabolism , Benzeneacetamides/immunology , Benzeneacetamides/pharmacology , Blotting, Western , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Cells, Cultured , Coculture Techniques , Cytarabine/immunology , Cytarabine/pharmacology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Fibroblasts/drug effects , Fibroblasts/metabolism , Flow Cytometry , Intercellular Adhesion Molecule-1/immunology , Intercellular Adhesion Molecule-1/metabolism , Lung Neoplasms/immunology , Lung Neoplasms/secondary , Melanoma, Experimental/genetics , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Ovalbumin/genetics , Ovalbumin/immunology , Ovalbumin/metabolism , Thiourea/analogs & derivatives , Thiourea/immunology , Thiourea/pharmacologyABSTRACT
Mechanisms of spontaneous tumor regression have been difficult to characterize in a systematic manner due to their rare occurrence and the lack of model systems. Here, we provide evidence that early-stage B cells in Eµ-myc mice are tumorigenic and sharply regress in the periphery between 41 and 65 days of age. Regression depended on CD4(+), CD8(+), NK1.1(+) cells and the activation of the DNA damage response, which has been shown to provide an early barrier against cancer. The DNA damage response can induce ligands that enhance immune recognition. Blockade of DNAM-1, a receptor for one such ligand, impaired tumor regression. Hence, Eµ-myc mice provide a model to study spontaneous regression and possible mechanisms of immune evasion or suppression by cancer cells.