Non-technical Abstract Hypoxia is an abnormal decrease of oxygen levels in tissues. Although different tissues and cells have distinct thresholds and susceptibility to hypoxia, at a cellular level, hypoxia and hypoxic responses generally occur at approximately 1-3 % oxygen. Compelling evidence has shown that reduced tissue oxygenation is present in various diseases, and more particularly cancer. A large number of human solid tumors profoundly lack oxygen, exhibiting hypoxic tumor areas; this condition is mainly due to an imbalance between delivery of oxygen via the blood circulation and consumption by cancer cells. Hypoxia can arise via a number of mechanisms. For instance, fast growing hypoxic tumors typically have poor vessel bio-distribution, increased vascular defects, and low vessel number. Furthermore, highly proliferating cancer cells that outgrow the neovascularization also participate in tumor hypoxia. An increasing list of cancers with hypoxic regions has been reported over the last decade and include endometrial carcinoma, ovarian, melanoma, lymphoma, breast, bladder, brain, head and neck, renal, colon, gastric, pancreatic, prostate, and non-small cell lung cancers. The research objective of this proposal is to apply standard methods of biomaterials science and engineering to emulate a hypoxic tumor microenvironment and better understand the interplay between tumor and dendritic cells, the major directors of immune responses. The proposed studies are likely to offer new modalities in cancer immunotherapy and are expected to justify the use of hypoxia-suppressive biomaterials, reinforce tumoricidal functions of immune cells, and ultimately increase tumor rejections. The educational goal of this proposal is to introduce biomaterials science and engineering to high school students (develop hands-on science curriculum, promote practical research experience, and foster STEM field trips to the campus), enhance undergraduate research exposure and experience to underrepresented students (Hispanic, African-American, and female), and expand the Northeastern University co-op model to include graduate and academic lab experiences.
Hypoxic cancers are usually aggressive, resistant to standard therapies, and thus very difficult to eradicate. A better understanding of how these hypoxic cancer cells interact with the immune system would allow tailoring of efficient therapies and better outcomes. Hypoxia can inhibit differentiation, antigen capture, maturation, lymph node homing of dendritic cells (DCs), the main regulators of immune responses, which can impair downstream T cell development, differentiation and cytotoxic activity. Immunosuppression represents one of the fundamental tumor immune evasion mechanisms. Therefore, it is important to expand our understanding on how hypoxia affects DCs and find ways to circumvent hypoxia-driven immunosuppression locally and restore immune cell function and activity. To address this need, the primary research objective of this proposal is to engineer biomaterials to modulate the local hypoxic environment to understand immune cell function and activity. To achieve this goal, this proposal has three aims: 1) Design injectable oxygen-generating cryogel scaffolds to controllably deliver oxygen, 2) Engineer a B16-F10 melanoma tumor microenvironment in three-dimension and deliver oxygen locally to modulate inherent and tumor-induced hypoxia, and 3) Disrupt hypoxia and modulate oxygen tension to understand how local oxygenation can regulate dendritic cell survival and function and impact their activity in an in-vitro ovalbumin (B16-F10/OVA) melanoma model. The long-term educational goal of the proposal is to promote and train the next generation of scientists to work in academia, industry and clinical settings developing innovative biomaterials to improve human quality of life. The major aims of this program are: 1) Introduce K-12 students to Biomaterials Science (develop a hands-on science curriculum, implement practical research experience, and foster STEM field trips to campus), 2) Enhance undergraduate research exposure and experience to underrepresented students (Hispanic, African-American, and female), and 3) Expand the Northeastern University co-op model to include graduate and academic lab experiences.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
