SUMMARY

Adoptive cell therapy (ACT) has emerged as a powerful treatment option for patients with metastatic melanoma. Despite encouraging results with this treatment modality, responses are seen in only a minority of patients. It is now known that low patient rates of response are due to poor tumor-infiltrating lymphocytes (TIL) survival post-transfer as well as poor trafficking of transferred cells to relevant tissues. For TILs to infiltrate disease tissue from the blood vasculature, they utilize a highly orchestrated adhesion cascade that begins with selectin-mediated rolling adhesion to endothelial cells, chemokine-triggered integrin activation, followed by integrin-mediated firm adhesion and subsequent extravasation. These adhesion ligand-receptor interactions have been implicated in TIL homing, however, an outstanding problem in the field is a lack of understanding of how TIL’s surface adhesion ligands initiate and sustain adhesion interactions within the tumor vasculature, and how this may lead to improved engraftment of TILs to the tumor microenvironment. As such, the overall objective of this project is to utilize engineered microfluidic devices that enable the interrogation of adhesive behavior of cells under relevant hemodynamic forces to 1) analyze how cell adhesion is regulated by different microenvironments of the tumor vasculature, 2) determine what adhesion receptors, cytokines, and activation markers are present in highly adhesive cells and 3) determine if high adhesivity leads to increase tumor engraftment and therapeutic effects. Using in vitro microfluidic devices that mimic the hemodynamic environment of the tumor vasculature, we have elucidated the cellular characteristics of CD8+ T cells associated with selectin-mediated adhesion in flow. This work will provide insight into which subpopulation of CD8+ T cells is the most appropriate for enhanced tumor homing for ACT.