Perelman School of Medicine at the University of Pennsylvania

Penn Institute for Immunology

Wayne William Hancock

faculty photo
Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
916B Abramson Research Center
3615 Civic Center Blvd.
Philadelphia, PA 19104-4318
Office: (215) 590-8709
Fax: (215) 590-7384
Education:
M.B.B.S. (Medicine)
Monash University, Clayton, Victoria, Australia, 1977.
Ph.D. (Medicine)
Monash University, Clayton, Victoria, Australia, 1984.
F.R.C.P.A. (Pathology)
Royal College o fPathologists of Australasia, 1989.
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Description of Research Expertise

Research Interests

Transplant immunobiology, inflammation and mechanisms of disease

Research Summary

New Co-Stimulation Molecules And Their Function In Vivo
The world is currently awash with costimulation molecules. Individual labs tout this or that molecule as being key to T cell activation under specific (often ludicrously specific) conditions, but none of these "insights" have yet led to actual therapeutic agents in clinical use. This reflects several factors. Drug companies make drugs and then try and find an application for them, ideally rheumatoid arthritis, multiple sclerosis, asthma or some other widespread disease involving long-term therapy, but certainly not any of the indications subject to the "too small a market (e.g. <$200 million dollars/year)" rule. Biologics are difficult and expensive to develop. Hence, the science underlying all the costimulation hype needs to examined critically if progress is to be achieved. Rather than adding more and more costimulation molecules to the list and thinking they are all equally important such that the Immunology Today-type diagrams in peoples' minds becomes more and more complicated, some reality testing is called for, and may thereby lead to new therapeutic approaches. Transplant models provide particularly advantageous systems to test the importance of such costimulation pathways using knockouts and blocking monoclonal antibodies and fusion proteins. We are currently investigating ICOS/B&RP-1; PD-1 and its ligands, PD-L1 and PD-L2; B7-H3; BTLA and B7-H4; and several TNF/TNF-R superfamily pathways, i.e. those molecules which constitute the "next wave" on which immunologic hopes, careers and dreams typically seem to be pinned upon but which in this case, as a bonus, may also be "true".

Chemokines/chemokine receptors in allograft rejection vs. tolerance
If all the world is a stage than an organ transplant is from an immunologic perspective a gothic masterpiece wherein every component of the immune system boils and pokes its way into the limelight at some point or another and the challenge is to make sense of it all. Chemokines are small molecular weight chemotactic cytokines which bind and signal via G protein-coupled seven-transmembrane receptors expressed by most cell types. Of special interest to immunologists are those chemokine receptors which mediate T cell recirculation as well as those which mediate attraction to sites of immune stimulation, such as an organ transplant. This field has its problems, not the least of which is its dreaded new nomenclature which has only served to decrease rather than improve communication. Suffice to say that despite there being over 45 chemokines and at least 18 chemokine receptors, with countless assertions of biologic redundancy and "promiscuous" binding (which sound interesting but isn't in this case), the development and testing of knockout mice and availability of neutralizing mAbs for use in wild-type controls has provided some sense of insight into how these pathways work in vivo. Of the various pathways involved in allograft responses, the most important seems to be CXCR3, which is expressed by NK cells and activated T cells, and has 3 ligands: IP-10, Mig and I-TAC. Blockade of CXCR3 has a particularly powerful effect in reducing host alloresponses. The second most important appears to be CCR5, whose ligands are many but include MIP-1a, MIP-1b and RANTES. We continue to investigate the importance of these and additional chemokine/chemokine receptor pathways in experimental and clinical studies.

Selected Publications

Negorev D, Beier UH, Zhang T, Quatromoni JG, Bhojnagarwala P, Albelda SM, Singhal S, Eruslanov E, Lohoff FW, Levine MH, Diamond JM, Christie JD, Hancock WW, Akimova T.: Human neutrophils can mimic myeloid-derived suppressor cells (PMN-MDSC) and suppress microbead or lectin-induced T cell proliferation through artefactual mechanisms. Scientific Reports 8(1): 3135, February 2018.

Xu H, Dahiya S, Wang L, Akimova T, Han R, Zhang T, Zhang Y, Qin L, Levine MH, Hancock WW, Levin LS.: Utility of IL-2 complexes in promoting the survival of murine orthotopic forelimb vascularized composite allografts. Transplantation 102: 70-78, January 2018.

Kalin JH, Wu M, Gomez AV, Song Y, Das J, Hayward D, Adejola N, Wu M, Panova I, Chung HJ, Kim E, Roberts HJ, Roberts JM, Prusevich P, Jeliazkov JR, Roy Burman SS, Fairall L, Milano C, Eroglu A, Proby CM, Dinkova-Kostova AT, Hancock WW, Gray JJ, Bradner JE, Valente S, Mai A, Anders NM, Rudek MA, Hu Y, Ryu B, Schwabe JWR, Mattevi A, Alani RM, Cole PA.: Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. Nature Communications 9: 53, January 2018.

Wang F, Wang L, Wu J, Sokirniy I, Nguyen P, Bregnard T, Weinstock J, Mattern M, Bezsonova I, Hancock WW, Kumar S.: Active site-targeted covalent irreversible inhibitors of USP7 impair the functions of Foxp3+ T-regulatory cells by promoting ubiquitination of Tip60. PLoS One Page: e0189744, December 2017.

Huang J, Wang L, Dahiya S, Beier UH, Han R, Samanta A, Bergman J, Sotomayor EM, Seto E, Kozikowski AP, Hancock WW.: Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function. Scientific Reports 17: 8626, August 2017.

Akimova T, Zhang T, Negorev D, Singhal S, Stadanlick J, Rao A, Annunziata M, Levine MH, Beier UH, Diamond JM, Christie JD, Albelda SM, Eruslanov EB, Hancock WW.: Human lung tumor FOXP3+ Tregs upregulate four "Treg-locking" transcription factors. JCI Insight Page: pii: 94075, August 2017.

Woods DM, Woan K, Wang D, Sodré AL, Cheng F, Wang Z, Chen J, Powers J, Pinilla-Ibarz J, Yu Y, Weber J, Hancock WW, Seto E, Villagra A, Yu XZ, Sotomayor EM.: T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model. Blood 130: 146-155, July 2017.

Laskin BL, Jiao J, Baluarte HJ, Amaral S, Furth SL, Akimova T, Hancock WW, Levine MH, Reese PP, Beier UH.: The Effects of Tacrolimus on T-Cell Proliferation Are Short-Lived: A Pilot Analysis of Immune Function Testing. Transplantation Direct 3: e199, July 2017.

Bin Dhuban K, d'Hennezel E, Nagai Y, Xiao Y, Shao S, Istomine R, Alvarez F, Ben-Shoshan M, Ochs H, Mazer B, Li B, Sekine C, Berezov, A, Hancock W, Torgerson TR, Greene M I, Piccirillo CA.: Suppression by human FOXP3+ regulatory T cells requires FOXP3-TIP60 interactions. Science Immunology 2,: eaai9297, June 2017.

Angelin A, De Gomez LG, Dahiya S, Jiao J, Guo L, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Wang W, Laskin BL, Blair IA, Wallace DC, Hancock WW, Beier UH. : Foxp3 reprograms T cell metabolism to function in low glucose high lactate environments. Cell Metabolism 25: 1282-1293, June 2017.

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Last updated: 02/19/2018
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