Bencherif Receives NSF CAREER Award
A $620K NSF CAREER award supports ChE Assistant Professor Bencherif research proposal on "Modulating Local Tumor Hypoxia using Cryogel Scaffolds to Regulate Dendritic Cell Function and Activity" for a five-year period from 2019 through 2024. The Faculty Early Career Development Program (CAREER) award from the National Science Foundation (NSF) is the foundation’s most prestigious honor for junior faculty members who exemplify the role of teacher-scholars through outstanding research, excellent education and the integration of education and research within the context of the mission of their organizations.
Source: News @ Northeastern
Photo: Sidi Bencherif, an assistant professor of chemical engineering, recently received a CAREER award from the National Science Foundation to develop biomaterials that generate oxygen. These materials could help researchers understand how low oxygen environments affect the immune system and potentially be used to supply oxygen to help train immune cells to fight cancer. Photo by Adam Glanzman/Northeastern University
by Laura Castañón, April 4, 2019
One of the reasons cancer is so hard to treat is that cancerous cells come from our own bodies. Our immune system has trouble distinguishing them from healthy cells.
“We can teach our immune system to attack cancer cells,” says Sidi Bencherif, an assistant professor of chemical engineering, but to do their job, immune cells need a steady supply of oxygen.
When cancer cells form tumors, their growth outpaces the available oxygen, creating hypoxic (low oxygen) areas. In a hypoxic environment, cancer cells can adapt their metabolism to survive, and even become more aggressive. But immune cells struggle to function.
“When immune cells come to the site to try to kill the tumor cells, they just can’t,” Bencherif says. “They are inhibited, because they are not used to being in a such immunosuppressive hypoxic environment.”
To study how low-oxygen environments alter the various functions of immune cells and ways to reverse it, Bencherif has designed a porous, gel-like material that gives off oxygen. He recently received a CAREER award from the National Science Foundation’s Faculty Early Career Development Program to support this work.
Bencherif did not originally build the gels to produce oxygen. He designed them as part of a cancer vaccine: microenvironments which would be loaded with cancer cells along active biomolecules and injected under the skin to act as training camps for immune cells. The porous gels would attract and activate dendritic cells (the information-gathering spies of the immune system), expose them to cancer cells so they knew what to target, and then send them back to the lymph nodes to share that knowledge with T-cells (the little soldiers in the body).
“It really is a lot like a training camp: recruit, train, activate and release,” Bencherif says. “And when we release dendritic cells, they will activate T-cells and mount a strong and specific immune response against cancer.”
But a gel filled with cancer cells acts a lot like a tumor—it creates a low-oxygen environment, which could make it harder for the dendritic cells do their jobs.
“Even if you are recruiting immune cells and trying to educate them, if you have a hypoxic environment, you’re not going to trigger a strong immune response,” Bencherif says. “You have to overcome hypoxia first.”
Now Bencherif has incorporated small particles that react with water into the matrix of the gels. This reaction produces a steady supply of oxygen. The oxygen-producing gels will allow him to study how an oxygen-rich environment affects the various functions of dendritic cells as they interact with hypoxic cancer cells.
“This is basic science. I’m trying to understand how these immune cells are affected by the tumor microenvironment and, if they are inhibited, how can we reverse it,” Bencherif says. “Down the road, this research may help us to make a better vaccine and potentially save millions of lives”.
Abstract Source: NSF
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.