Recording and Reprogramming Neuroimmunity in Cancer
Author(s)
Tabet, Anthony
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Advisor
Anikeeva, Polina
Wittrup, K. Dane
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Adult and pediatric glioblastomas are incurable and universally lethal, with a median survival under 15 months. Despite this overwhelming unmet medical need, therapies developed over the last three decades have been unable to extend patient lifetime beyond a few months. These therapies, which include the small molecule chemotherapies carmustine and temozolimide, photodynamic therapy, tumor-treating fields and others, attempt to treat brain tumors by disrupting processes important for proliferation of cancer cells. A brain tumor, however, is not just a collection of cancer cells. Neurons and immune cells in the tumor microenvironment are reprogrammed to support tumor growth and are critical in disease progression. Yet therapies targeting these two compartments have been slower to enter the clinic. Much remains unknown about how cancer cells reprogram their neuronal and immune microenvironments, and how this program changes cellular phenotype to support cancer proliferation.
Over the last five years, new studies suggest that disrupting the underlying neuroimmune profile of tumors can inhibit progression. Targeting tumor-associated neurons and immune cells, which are indispensable for cancer proliferation, instead of simply disrupting cell division in a subset of cancer cells is a promising therapeutic strategy. Yet it remains challenging to perform biologically precise experiments in vivo, and there is no toolkit available for chronic recording or modulation of these cell signaling cascades.
In this thesis, we deploy implantable or injectable materials which transmit signals the nervous and immune systems are responsive to. These materials can modulate both systems within a murine brain tumor chronically in vivo. Soft, polymer-based hydrogel bioelectronic neural interfaces are used to deliver electrical, optical, or chemical stimuli for bidirectional interfacing with the neuron-cancer axis. Engineered cytokines tethered to a nanoparticle-based adjuvant allow for safe modulation of the tumor immune compartment with significant survival benefit. Together, these technologies comprise a toolkit which can be used to study how neurons and immune cells contribute to brain tumor progression, enabling us to precisely interrogate the neuro-immune-cancer axis chronically in vivo.
Date issued
2023-02Department
Massachusetts Institute of Technology. Department of Chemical EngineeringPublisher
Massachusetts Institute of Technology