The overarching goal of our research program is to investigate the molecular mechanisms that control lymphocyte trafficking across blood vessel walls which are important checkpoints in the development of a fine-tuned adaptive immune response. These studies are particularly relevant to cancer immunotherapy since it is now recognized that the extent of T cell infiltration at tumor sites is a critical determinant of patient responses to immune-based therapies as well as standard chemotherapy and radiation.
Using live-imaging microscopy we have definitively shown that poor baseline trafficking of cytotoxic effector T cells within tumor lesions represents a significant bottleneck to antitumor immunity and immunotherapy. One informative avenue of research has focused on the thermal element of fever as a model of acute inflammation. Our studies reveal that fever-range thermal stress or high-temperature ablative therapy has a profound influence on the delivery of blood-borne lymphocytes to lymphoid organs and tumor tissues.
These observations led to the discovery of a previously unrecognized role for the proinflammatory cytokine, interleukin-6, in boosting trafficking of blood-borne lymphocytes to lymphoid organs or tumor tissues during acute inflammation and vascular-targeting preconditioning regimens for cancer immunotherapy. Our preclinical findings regarding the mechanistic underpinnings of tumor-stromal-immune system interactions have guided several Phase I and Phase II clinical trials, including the development of an intraoperative intravital imaging platform for the study of tumor vessel function in cancer patients in real time.
Current studies are exploring new avenues to modify the adhesive landscape of tumor vessels in order to improve the access of cytolytic effector T cells to neoplastic targets in the local environment.
Molecular Mechanisms Controlling Lymphocyte Trafficking