Breast Cancer Cell Uptake of the Inflammatory Mediator Neutrophil Elastase Triggers an Anticancer Adaptive Immune Response

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 pathobiological basis for the prognostic significance of neutrophil elastase (NE), a serine protease found in neutrophil granules, in a model of cyclin E-overexpressing breast cancer. We established that NE was expressed by TAN within breast cancer tissues but not by breast cancer cells. NE modulated killing of breast cancer cells by cytotoxic T lymphocytes (CTL) specific for cyclin E-derived HLA-A2 restricted peptide (ILLDWLMEV). Breast cancer cells exhibited striking antigen-specific uptake of NE from the microenvironment that was independent of NE enzymatic activity. Further, NE uptake increased expression of low molecular weight forms of cyclin E and enhanced susceptibility to peptide-specific CTL lysis, suggesting that cyclin E 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.

Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma

“…In that study, we were also able to show that NE entered tumor cells, which resulted in the elimination of intracellular IRS-1. Since the time of that report, NE has been shown to enter multiple different cancer cell types, including breast cancer (30,31). NE also enters nonmalignant cells, such as fibroblasts (32) and hepatocytes (33), both of which caused the loss of intracellular IRS-1.…”

Clathrin Pit-mediated Endocytosis of Neutrophil Elastase and Cathepsin G by Cancer Cells

“…Our report represents the first description of a secreted proteinase gaining access to another cell without killing it, as is the case with the granzymes, for example. Subsequently, NE has been shown to enter into breast cancer cells as well (18).…”

Enzyme-activatable imaging probe reveals enhanced neutrophil elastase activity in tumors following photodynamic therapy

“…This novel observation along with other recent findings therefore demonstrates that extracellularly released NE has physiologic functions that contribute to host defense, and hence the conventional view that assigns NE as pathogenic for tissue-destructive diseases, such as acute or chronic pulmonary diseases, warrants careful reassessment. 13,28 Further, as PDT induces increased accumulation of neutrophils in treated tumors and NE is released from activated neutrophils and stimulates proinflammatory cytokines, our characterization of significant NE increase in PDT-treated tumors establishes a rationale to further evaluate a previously undescribed role of NE in linking the elements of innate and adaptive host response associated with PDT.…”

“…10 Serine proteases released from activated neutrophils have emerged as a major player in the regulation of inflammatory response, such as specifically altering the function of cytokines and chemokines. 11 Mittendorf et al 28 recently showed that a novel breast cancer antigen, Cyclin E, is cleaved after specific uptake of NE by breast cancer cells, and this increases the susceptibility of the cancer cells to lysis by cytotoxic T lymphocytes-specific for the antigen. This novel observation along with other recent findings therefore demonstrates that extracellularly released NE has physiologic functions that contribute to host defense, and hence the conventional view that assigns NE as pathogenic for tissue-destructive diseases, such as acute or chronic pulmonary diseases, warrants careful reassessment.…”