Neutrophil Extracellular Traps and the Intersection of the Immune and Biophysical Microenvironments

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Project Summary: While immunotherapy has revolutionized cancer treatment in recent years, major challenges still remain. Metastatic cancer remains difficult to treat, resulting in 90% of cancer deaths, and only 20-40% of patients respond to immunotherapy, with varying levels of response across cancers. In solid tumors, lymphatic activation, or lymphangiogenesis, is associated with both metastasis and improved response to immunotherapy, and more recently, neutrophil activation has also emerged as playing a key role in both of these processes. An important mechanism by which neutrophils promote cancer progression is through the formation of neutrophil extracellular traps (NETs). NETs are a mesh network of decondensed DNA dotted with histones and granular proteins, and they are released by neutrophils in order to trap and kill pathogens, or in response to tumor-secreted cytokines. Many of these proteins are proteases, which have the potential to remodel the extracellular matrix (ECM). In this proposal, we will explore the novel hypothesis that lymphatics and neutrophils collaborate in driving pro-metastatic programs in ways that alter the extracellular matrix (ECM) and host immune response. We will use immunofluorescence staining and second harmonic generation imaging of tumors, lungs, and lymph nodes from 4T1 and B16 murine models of cancer to characterize the cross-talk between NETosis, lymphangiogenesis and ECM in cancer metastasis. We will also use an inducible model of lymphangiogenesis that is specific to the lung in order to determine if the effect of NETosis on metastasis is specific to the pre-metastatic niche or the tumor microenvironment. We will use physiological artificial ECM and 3D perfusion models of the tumor-lymph node microenvironment with ex vivo tissues to determine how the biophysical properties of the tumor microenvironment affect NETosis and T cell cytotoxicity, and how NETosis affects tumor progression and response to immunotherapy. Results from this work could help us better predict which patients are likely to respond to immunotherapy and lead to new therapeutic strategies that make immunotherapy more effective in more patients. It will also increase our understanding of how the biophysical properties of the microenvironment affect immune cell function in general, which is likely an important factor in many disease processes.