ABSTRACT
There is little understanding of the impact of tumor-associated neutrophils (TAN) on adaptive immunity to tumors. In this study, we report the results of an investigation of the pathobiologic basis for the prognostic significance of neutrophil elastase, a serine protease found in neutrophil granules, in a model of cyclin E (CCNE)-overexpressing breast cancer. We established that neutrophil elastase was expressed by TAN within breast cancer tissues but not by breast cancer cells. Neutrophil elastase modulated killing of breast cancer cells by CTLs specific for CCNE-derived HLA-A2-restricted peptide (ILLDWLMEV). Breast cancer cells exhibited striking antigen-specific uptake of neutrophil elastase from the microenvironment that was independent of neutrophil elastase enzymatic activity. Furthermore, neutrophil elastase uptake increased expression of low molecular weight forms of CCNE and enhanced susceptibility to peptide-specific CTL lysis, suggesting that CCNE peptides are naturally presented on breast cancer cells. Taken together, our findings reveal a previously unknown mechanism of antitumor adaptive immunity that links cancer cell uptake of an inflammatory mediator to an effective cytolytic response against an important breast cancer antigen.
Subject(s)
Breast Neoplasms/pathology , Inflammation Mediators/metabolism , Leukocyte Elastase/metabolism , Adaptation, Physiological , Amino Acid Sequence , Base Sequence , Breast Neoplasms/enzymology , Breast Neoplasms/immunology , Breast Neoplasms/metabolism , DNA Primers , Female , Humans , Immunohistochemistry , Molecular Sequence Data , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Advances in the molecular characterization of human tumors have led to increased interest in the development of targeted therapeutics to include cancer vaccines. The recent success of sipuleucel-T, an autologous cellular vaccine administered to patients with hormone-refractory metastatic prostate cancer, suggests that this is a viable therapeutic option in the management of patients with solid tumors. This article focuses on breast cancer vaccines emphasizing delivery platforms, target antigens and novel strategies designed to enhance response to vaccination that are being evaluated in ongoing Phase II clinical trials.
