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
Chen Q, Wang WC, Bruce R, Li H, Schleider DM, Mulbury MJ, Bain MD, Wallace PK, Baumann H, Evans SS. Central role of IL-6-receptor signal transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. Immunity. 2004 20:59-70. [See also preview article by Rose-John S, Neurath MF, “IL-6 trans-signaling: the heat is on”, Immunity. 2004 20:2-4]. PMID: 14738765
Chen Q, Fisher DT, Clancy KA, Gauget JM, Wang WC, Unger E, Rose-John S, von Andrian UH, Baumann H, Evans SS. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nature Immunol. 2006 7:1299-1308. [See also Bromley SK, Luster AD. News & Views: Turning up the heat on HEVs. Nature Immunol. 2006 7:1288-1290; Ledford H. Research highlights: Hot-blooded. Nature. 2006 444:126; Kaiser J. Don’t fight the fever. ScienceNOW, Nov. 2006] PMID: 17086187
Appenheimer MM, Girard RA, Chen Q, Wang WC, Bankert KC, Hardison J, Bain MD, Ridgley F, Sarcione EJ, Buitrago S, Kaspers B, Rose-John S, Baumann H, Evans SS. Conservation of IL-6 trans-signaling mechanisms controlling L-selectin adhesion by fever-range thermal stress. Eur J Immunol. 2007 37:2856-2867. [See also In This Issue: If you’re sick, turn up the heat! Hundreds of years of evolution can’t be wrong. Eur. J. Immunol. 2007 37:2674]. PMID: 17823890
Fisher DT, Chen Q, Skitzki JJ, Muhitch JB, Zhou L, Appenheimer MM, Vardam TD, Weis EL, Passanese J, Wang WC, Gollnick SO, Dewhirst MW, Rose-John S, Repasky EA, Baumann H, Evans SS. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest. 2011 121:3846-59. PMC3195455
Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nature Reviews Immunology. 2015. 15(6):335-49. PMC4786079
Mikucki ME, Fisher DT, Matsuzaki J, Skitzki JJ, Gaulin NB, Muhitch JB, Frelinger JG, Odunsi K, Gajewski TF, Luster AD, Evans SS. Non-redundant requirement for CXCR3 signaling during tumoricidal T cell trafficking across tumor vascular checkpoints. Nature Communications. 2015 6, Article number: 7458. PMC4605273
Fisher DT, Muhitch JB, Kim M, Doyen KC, Bogner PN, Evans SS, Skitzki JJ. Intraoperative intravital microscopy permits the study of human tumour vessels. Nature Communications. 2016 7, Article number: 10684. PMC:In process