Despite advances in drug discovery and early diagnosis, cancer remains the second leading cause of death worldwide. Recent breakthroughs have demonstrated good clinical outcomes in a number of difficult-to-treat cancers, but response rates have been variable and many treatments result in unwanted side effects. Thus, there is an emerging interest in developing therapies that enhance the ability of the body's own Natural Killer (NK) cells, which are immune system cells that have the ability to recognize cancer cells and destroy them. Unfortunately, tumors create a local environment, called the tumor microenvironment, that suppresses the functions of the NK cells and thereby allows the cancer to grow unchecked. The goal of this Faculty Early Career Development Program (CAREER) project is to engineer three-dimensional models of the tumor microenvironment and to interrogate the biochemical and mechanical cues that impact how NK cells migrate into tumors and recognize cancer cells. The knowledge generated by these studies could lead to new therapeutic targets or strategies for NK cells to overcome the immunosuppressive tumor microenvironment and attack cancer cells. The research project will provide graduate and undergraduate students with interdisciplinary training at the cutting edge of tumor biology, immunology, and tissue engineering. The education goals of the project are to develop curricula and outreach activities that will excite students at the K-12, undergraduate, and graduate levels about the impact of science, technology, engineering, and math (STEM) professions on their local communities and society as a whole. In particular, outreach activities aimed at increasing awareness of the breath of opportunities that a STEM education provides will be targeted to middle school students and teachers in underserved and economically disadvantaged schools in north-central Florida.
The goal of this project is to develop engineered tumor microenvironments to interrogate the biochemical and mechanical cues that impact Natural Killer (NK) cell migration and activity. Unlike T-cells, NK cells can function in an antigen independent manner by recognizing "stress signals" and alterations in cell surface ligands on nascent tumor cells that correspond to activating receptors on NK cells. Adoptive cell transfer of NK cells has demonstrated promise in eradicating certain hematological malignancies; however, solid malignancies have proved more challenging. To exert their effector functions in solid tumors, NK cells must migrate through the tumor stroma and make cell-to-cell contact with cancer cells. While much research is focused on enhancing NK cell activation at the NK cell-cancer cell synapse, without sufficient NK cell infiltration these strategies may ultimately be inefficient/ineffective. The first objective of the research plan is to engineer a tunable 3-D culture system to investigate how NK cell-ECM interactions impact NK cell recruitment. Various poly(ethylene glycol)-based hydrogels will be engineered with tunable physical and biochemical properties such as stiffness, cell adhesion sites, enzymatic degradation sites, and tumor-related proteoglycans to interrogate the biochemical and mechanical cues that impact NK cell recruitment. The working hypothesis is that ECM composition and stiffness will impact NK cell migration and activation in response to chemotactic gradients. The extent of NK cell migration, the mechanism of migration, and cytokine production will be assessed in the engineered microenvironments. The second objective of the research plan is to characterize how the extracellular microenvironment impacts NK cell-cancer cell interactions. Tumor immunosuppression mechanisms and NK cell-cancer cell interactions will be examined in physiologically relevant 3-D systems. The working hypothesis is that the composition and stiffness of the ECM influences the immunosuppressive mechanisms in tumors and, consequently, NK cell-cancer cell interactions. The results from these studies will advance the field of cancer immunotherapies and lead to new strategies for NK cell therapies in solid malignancies as well as new in vitro tools for evaluating their effectiveness.
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.
