Abstract 2103: NETs promote tumor resistance to anthracyclines

Abstract

Abstract Multiple Myeloma (MM) is an incurable blood cancer characterized by the clonal proliferation of plasma cells that accumulate in the bone marrow (BM). Resistance to chemotherapy represents one of the main challenges in the treatment of this disease. We have previously shown that neutrophils, one of the major cellular populations in the BM, protect MM cells from chemotherapies including anthracyclines; however, the mechanisms of this effect remain unknown. Thus, we set out to investigate the mechanisms by which neutrophils reduce sensitivity of tumor cells to anthracyclines. Neutrophil extracellular traps (NETs) are structures composed of chromatin and protein formed by neutrophils that are a part of an innate immune mechanism of binding and killing pathogens. Recently, NETs have been shown to form in cancer patients as well as tumor-bearing animals and have been implicated in solid tumor progression; however, their role in hematological malignancies remain poorly understood. Utilizing an in vitro culture system, we demonstrated that MM cells were able to induce NET formation by BM neutrophils. Interestingly, neutrophils isolated from the BM of patients with MM have a significantly higher ability to produce NETs in response to tumor cells as compared to BM neutrophils from donors. NET formation was accompanied by an increase in the level of extracellular DNA. Using imaging flow cytometry and confocal microscopy we demonstrated that extracellular DNA is internalized by tumor cells and localizes to the cytoplasm. This internalized DNA was able to bind to doxorubicin and other anthracyclines thereby reducing their cytotoxic effects. Significantly increased cell-free DNA levels were detected in BM aspirates from MM patients as well as in tumor-bearing mice. Targeting the extracellular DNA in vivo using the clinically available DNase, Pulmozyme, restored the sensitivity of tumor cells to doxorubicin resulting in prolonged survival of tumor-bearing animals. Here, we have identified a novel mechanism of resistance to anthracyclines that is mediated by neutrophils in the tumor microenvironment and provided evidence to support the premise that targeting this mechanism would be of significant benefit in the treatment of MM. Citation Format: Cindy Lin, Sarah E. Herlihy, Marina Li, Hui Deng, Luca Bernabei, Dmitry I. Gabrilovich, Dan T. Vogl, Yulia Nefedova. NETs promote tumor resistance to anthracyclines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2103.