Interplay of natural killer cells and extracellular matrix proteins in solid cancers

Project Summary/Abstract: Natural killer (NK) cells have long been known to provide critical early defense against viral infections and malignancies. Nevertheless, most of the clinical success associated with using NK cells has been restricted to hematological malignancies, which can be partly attributed to the defective NK cell activation in peripheral tissues. Extracellular matrix (ECM) proteins are present in all peripheral tissues where they maintain homeostasis by providing scaffold as well as important developmental cues to the surrounding cells. We have recently discovered a critical role for ECM proteins in switching the function of conventional NK cells as they exit the circulation and enter the peripheral tissues. We aim to investigate how ECM proteins regulate NK cell functions in the skin and solid cancers. Skin and breast cancer are the leading cause of cancer morbidity and mortality in the United States. These cancers frequently develop primary and secondary resistance to current immunotherapeutics. In addition, chemotherapies for them cause wide-ranging side effects and thus significantly burden the health care system. Defective ECM turnover is a hallmark of skin, breast, and other solid cancers. To fully elucidate the bi-directional interactions between NK cells and ECM in the context of solid cancer development, we aim to (1) Determine the mechanism of collagen-induced loss of NK cell killing function in solid cancers, (2) Determine the role of collagen-III in the regulation of NK cell helper function in solid cancers, and (3) Examine the impact of other major ECM proteins on NK cell functionality. The outcomes of the proposed studies will reveal novel mechanisms of ECM-NK cell interactions in cancer. Our research will greatly facilitate the development of novel therapeutic strategies to harness NK cells for the treatment of solid cancers.