Neutrophil extracellular traps (aptly abbreviated NETs) are a result of NETosis, a unique form of regulated cell death. NETosis induces leukocytes (white blood cells) to essentially eject their insides out, casting a network of chromatin scaffolds, cytotoxic enzymes, and proteases into the extracellular space. As an immune defense, NETs trap pathogens like bacteria and fungi. Interestingly, in mouse models, NETs may promote tumor metastasis by shielding circulating tumor cells, mediating extracellular matrix degradation, and modulating the pre-metastatic niche. The presence of NETs and their ability to foster tumor progression in primary human tumor sites as well as pre-metastatic and metastatic niches, have been recently reported, yet the exact mechanisms are still unknown.
Ignacio Melero and his team have shown that the chemokine interleukin-8 (IL-8) supports neutrophil and myeloid-derived suppressor cell (MDSC) migration into the tumor microenvironment. They have also demonstrated that IL-8 induces NETosis in human granulocytic MDSCs and there are reports of a direct correlation of IL-8 production with increased tumor burden, metastasis, and overall poor outcomes. With this ASPIRE Award, Melero and his team will optimize novel immunoassays in serum and image-based detection and quantitation technologies for NETs in tumor tissue and serum specimens. These techniques will then be used to quantify and characterize NETosis in human tumor tissue, investigate immune infiltrates within tumors after inhibition or removal of NETosis, and to identify potential immunotherapy strategies in combination with checkpoint inhibitors. Elucidating the role of IL-8 in NETosis and cancer could provide a new biomarker and pathway for innovative cancer therapies.
Olivera I, Sanz-Pamplona R, Bolaños E, Rodriguez I, Etxeberria I, Cirella A, Egea J, Garasa S, Migueliz I, Eguren-Santamaria I, Sanmamed MF, Glez-Vaz J, Azpilikueta A, Alvarez M, Ochoa MC, Malacrida B, Propper D, de Andrea CE, Berraondo P, Balkwill FR, Teijeira Á, Melero I. A Therapeutically Actionable Protumoral Axis of Cytokines Involving IL-8, TNFα, and IL-1β. Cancer Discov. 2022.
Olivera I, Bolaños E, Gonzalez-Gomariz J, Hervas-Stubbs S, Mariño KV, Luri-Rey C, Etxeberria I, Cirella A, Egea J, Glez-Vaz J, Garasa S, Alvarez M, Eguren-Santamaria I, Guedan S, Sanmamed MF, Berraondo P, Rabinovich GA, Teijeira A, Melero I. mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy. Cell Rep Med. 2023.