Escape of myeloma cells from CD4 T-cell-driven immunoprotection (P2015)

Abstract

Abstract Background: CD4+ T cells can mediate efficient immunosurveillance against MHC class II-negative cancer cells through indirect presentation of tumor-specific antigens on antigen-presenting cells (APCs). A CD4+ T cell response against an epitope on the immunoglobulin light chain of the Id peptide of MOPC315 myeloma cells can mediate an antitumor immune response that induces long term tumor dormancy, followed by eventual tumor escape. Interestingly, this escape occurs despite continued secretion of the tumor-specific antigen. Objective: To identify the immunoediting mechanisms underlying the loss of T-cell-mediated immunoprotection against MOPC315 myeloma cells Method: Mice injected with fluorescently labeled MOPC315 tumor cells were monitored using in vivo imaging. Parental and escape tumor cell clones were obtained, and gene- and protein expression characterized. Results: Escape tumor cells secrete an intact M315 Id peptide, but secretion of free light chains is selectively down-regulated. This limits exposure of the inciting antigen in a form that permits efficient antigen display by tumor-infiltrating APCs, despite preserved T cell reactivity within draining lymph nodes. Our study defines a novel mechanism of tumor immunoevasion by modified secretion of a natural tumor-specific antigen, which emphasizes the importance of antigen presentation within the tumor microenvironment, and has implications for the design of effective CD4+ T cell-based immunotherapy.