About

Wayne William Hancock, MB.BS, PhD, FRCPA, is a Professor of Pathology and Laboratory Medicine at the University of Pennsylvania's Perelman School of Medicine. He is an investigator at the Biesecker Pediatric Liver Center at The Children's Hospital of Philadelphia and a member of multiple research centers including the Penn Diabetes Center, Abramson Cancer Center, Penn Center for Clinical Immunology, Penn Cardiovascular Center, Rheumatic Diseases Core Center, Institute for Translational Medicine and Therapeutics, Institute for Immunology, Penn Program in Epigenetics, Center for Mitochondrial and Epigenomic Medicine, Penn-CHOP Lung Biology Institute, and the Institute for RNA Innovation. His research focuses on transplant immunobiology, inflammation, mechanisms of disease, Treg cells, cancer immunology, and therapeutics. He has contributed to understanding co-stimulation molecules, chemokine pathways in allograft rejection, and immune responses in transplantation, with numerous publications in the field.

Research topics

• Internal medicine
• Cancer research
• Cell biology
• Biology
• Biochemistry
• Medicine
• Endocrinology

Selected publications

• Hemodynamic forces prevent myxomatous valve disease through KLF2/4 signaling

  Journal of Molecular and Cellular Cardiology Plus · 2026-03-01

  articleOpen access
  PublisherDOI

• Targeting the APRIL-BAFF axis in IgA nephropathy: preclinical insights from influenza challenge and single-cell spatial profiling

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-06

  articleOpen access

  ABSTRACT Background APRIL and BAFF are TNF superfamily cytokines that regulate B-cell development, survival, and antibody production, and are emerging therapeutic targets for IgA nephropathy (IgAN). Selective APRIL and dual APRIL/BAFF inhibitors both reduce IgA and proteinuria in IgAN clinical trials, but whether their broader immunological consequences differ has not been systematically characterized. Methods We compared selective APRIL and dual APRIL/BAFF inhibition using influenza vaccination and lethal challenge, KLH immunization, serological profiling, and flow cytometry in mice, alongside human B-cell survival assays in vitro. Single-cell CITE-seq and in situ spatial transcriptomics were applied to characterize molecular and tissue-level changes in the spleen. Results Both modes of inhibition reduced serum IgA by ≥60% in mice. However, dual APRIL/BAFF inhibition nearly abolished vaccine-mediated protection against lethal influenza challenge (10% versus 70% survival in controls; p < 0.01), whereas selective APRIL inhibition had limited impact on protective immunity. This functional divergence was underpinned by broad cellular disruption under dual blockade, including >80% depletion of splenic B cells, loss of T follicular helper cells, and impaired antigen-specific IgM and IgG responses. Selective APRIL inhibition left these populations and responses largely intact. Consistent with these findings, human B-cell survival in vitro was dependent on BAFF, not APRIL. Single-cell and spatial transcriptomics revealed that dual blockade collapsed follicular architecture, eliminated germinal centers, and disrupted chemokine organization, whereas these structures remained intact under selective APRIL inhibition. At the molecular level, dual blockade, but not selective APRIL inhibition, downregulated NF-κB survival signaling and antigen presentation programs and shifted surviving germinal center B cells toward a pro-apoptotic state. Conclusions Selective APRIL and dual APRIL/BAFF inhibition both reduce IgA, the pathologically relevant isotype in IgAN, but only dual blockade disrupts B-cell maturation, germinal center function, tissue architecture, and protective immunity. These findings inform the benefit-risk assessment of chronic B cell-targeting therapies in IgAN.

  PublisherDOI

• Abstract 2252: ASO targeting of intratumoral human FOXP3+ Tregs in humanized SGM3-IL15 mice

  Cancer Research · 2025-04-21

  article1st authorCorresponding

  Abstract Introduction: Humanized mice are an indispensable tool for pre-clinical cancer immunotherapy research, but there are limited data regarding human antitumor T cell immunity in such models, especially regarding the development of intratumoral T cell exhaustion. Methods: We wanted to develop a Treg-dependent tumor model in humanized mice to study the effect of AUMsilence FOXP3 antisense oligonucleotides (ASO) targeting of intratumoral human CD4+ FOXP3+ regulatory T cells (Tregs) in vivo. The ideal model would support development and function of human Tregs, CD4+ and CD8+ T cells, allow tumor growth without apparent allogeneic reactivity, demonstrate the development of a suppressive tumor microenvironment, including with exhaustion of tumor-infiltrating T cells, and prove to be a Treg dependent tumor model. To do so, we evaluated two novel JAX strains of humanized CD34+ engrafted mice, NSG-SGM3 and NSG-SGM3-IL15. Results: Both strains of mice had high (>80%) reconstitution by human CD45+ cells, no signs of GVHD, and increased proportions of FOXP3+ Tregs in their spleens, blood and livers (23-35% of CD4+ cells). Suppressive function of isolated liver and splenic Tregs were comparable with healthy donor blood Tregs. Both strains of mice supported similar growth of A549 lung tumor cells without rejection, and tumors were infiltrated by human CD45+ cells (8-20%), including 15-35% of FOXP3+ Tregs. Expression of T cell exhaustion markers was observed in tumors, but not in spleens, livers or blood. FOXP3 ASO treatment resulted in a decrease in tumor growth, while scramble treated mice developed multiple lung metastases and larger tumors. FOXP3 expression was also decreased in tumors (2.7 times, p =0.02) but not in the spleens and livers of ASO treated mice. Of note, targeting of intratumoral Tregs led to decreased expression of most T cell exhaustion markers in tumors, confirming our previous report that intratumoral Treg may promote T cell exhaustion. Conclusions: NSG-SGM3 and NSG-SGM3-IL15 mice provide a platform for preclinical drug testing involving an immunosuppressive tumor microenvironment and accumulation of exhausted T cells and fully functional Tregs. AUMsilence FOXP3 ASO therapy has powerful anti-tumoral effects in vivo, decreases metastases and reverses features of T cell exhaustion. Citation Format: Wayne W. Hancock, Tatiana Akimova, Liqing Wang, Zhanna Bartosh, Lanette M. Christensen, Pali Kaur, Veenu Aishwarya. ASO targeting of intratumoral human FOXP3+ Tregs in humanized SGM3-IL15 mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2252.

  PublisherDOI

• #1035 Differential impacts of APRIL and APRIL/BAFF inhibition on immune populations: implications for IgAN treatment and protective immunity

  Nephrology Dialysis Transplantation · 2025-10-01

  articleOpen access

  Abstract Background and Aims APRIL and BAFF are essential cytokines for B cell and plasma cell development and survival. Inhibition of APRIL or APRIL/BAFF has emerged as a promising strategy for the treatment of kidney and other immune-mediated diseases, yet their broader impacts on immune homeostasis remain incompletely understood. Given the importance of B cells in immunity, such inhibition may pose risks of immunosuppression and increase susceptibility to infection. Hence, we characterized the differential effects of APRIL and APRIL/BAFF inhibition on immune cell populations, serological responses, and protective immunity in mouse models. Method Mice were dosed twice per week with anti-APRIL antibody (4540), or APRIL/BAFF inhibitors (TACI-Fc fusion proteins POV and ATA, based on the sequences of povetacicept and atacicept, respectively), or isotype control antibody (MOTA). Serum immunoglobulin levels (IgA, IgM, and IgG) were quantified weekly by ELISA. Comprehensive immunophenotyping was performed on splenocytes harvested 8 weeks after initial dosing to characterize B and T cell populations. Single cell RNA sequencing and spatial transcriptomics were performed on mouse splenocytes. Results Repeated dosing of mice with anti-APRIL mAb 4540 did not significantly reduce B-cell or antibody secreting cell (ASC) subsets, except for splenic germinal center B cells. Conversely, both dual APRIL/BAFF inhibitors led to a reduction of total B cells (up to 89%) and most B cell subsets, including ASCs (Fig. 1A). Follicular B cells were reduced by APRIL/BAFF inhibitors and exhibited lower CD21/35 expression (Fig. 1B), suggesting an abrogation of maturation and proliferation potential. APRIL and APRIL/BAFF inhibition had minimal impact on most T cell populations. APRIL/BAFF dual inhibitors, but not anti-APRIL antibody, led to a reduction in T follicular helper (Tfh) cells, an observation consistent with BAFF promoting development of Tfh cells (Fig. 1A). Single cell and spatial transcriptomic analyses supported these observations across B and T cell compartments with further characterization of cell state and pathway changes. Serology measurements from the same treated mice demonstrated both classes of inhibitors yielded ≥40% reduction in IgA. The APRIL/BAFF inhibitors also reduced IgM and IgG by ≥60% and ≥20%, respectively. APRIL-only inhibition did not reduce IgM or IgG (Fig. 2). Within the mouse, we present the implications of these immune cell changes to protective immunity against respiratory viruses. Conclusion This study demonstrates that administration of both APRIL and APRIL/BAFF inhibitors reduce serum IgA, a desirable effect for kidney diseases like IgA nephropathy, in which elevated levels of aberrantly glycosylated IgA have a pathogenic role. However, dual APRIL/BAFF inhibition leads to significant ablation of most B cell subsets, ASCs, and Tfh cells, whereas APRIL-only inhibition does not substantially alter splenic cell populations. Broad immune cell ablation has implications for immune homeostasis and responses to vaccines and pathogens. Ongoing animal studies will extend these analyses of APRIL and APRIL/BAFF inhibition to multiple vaccine and viral challenge models.

  PublisherOA PDFDOI

• Differential effects of HDAC8 targeting on Foxp3+ Tregs and effector T cells promote antitumor immunity

  JCI Insight · 2025-12-11

  articleOpen accessSenior author

  HDAC8, an evolutionarily distinct, X-linked, zinc-dependent class I histone/protein deacetylase, is implicated in developmental disorders, parasitic infections, myopathy, and cancers. Our study demonstrates the important role of HDAC8 in immune cells by conditional targeting of HDAC8 in murine T cells and application of selective HDAC8 inhibitors. Using flow cytometry, RNA-seq, and ChIP-seq analyses, we demonstrate that knocking down or inhibiting HDAC8 impaired murine regulatory T cell (Treg) suppressive function in vitro and in vivo, but promoted conventional host T cell responses, thereby limiting syngeneic tumor growth. Mechanistically, HDAC8 knockout downregulated Foxp3 expression, enhanced H3K27 acetylation levels, and promoted IL-2, IL-6, Fas, and FasL expression in both Treg and conventional effector T cells. Thus, our combined genetic and pharmacologic studies establish the central importance of HDAC8 in T cell responses and suggest that selective HDAC8 inhibitors represent a potential therapeutic approach in immuno-oncology.

  PublisherOA PDFDOI

• Five Strategies to Use IL-2 Muteins to Expand Foxp3+ Treg Cells and Promote Long-Term Cardiac and Renal Allograft Survival in Naïve and Sensitized Recipients

  American Journal of Transplantation · 2025-08-01

  articleSenior author
  PublisherDOI

• Class <scp>IIa HDACs</scp> forced degradation allows resensitization of oxaliplatin‐resistant <scp>FBXW7</scp> ‐mutated colorectal cancer

  Molecular Oncology · 2025-10-31

  articleOpen access

  Epigenetic plasticity and large-scale chromatin remodeling characterize tumor evolution and the emergence of subclones resistant to conventional therapies. Catalytically inactive class IIa HDACs (HDAC4, HDAC5, HDAC7, HDAC9) control the targeted recruitment of chromatin remodeling complexes, making them attractive therapeutic targets in oncology. In this study, we found that HDAC4 is degraded by the proteasome in cancer cells with impaired DNA repair by homologous recombination and after oxaliplatin (OXPT) treatment. Genetic screening identified FBXW7 as the E3 ligase responsible for HDAC4 degradation. FBXW7 loss-of-function mutations are frequently found in patients with colorectal cancer (CRC) and were found associated with the development of resistance to OXPT. Forced degradation of Class IIa HDACs using a PROTAC-based compound restored OXPT sensitivity in FBXW7-mutated CRC cells, patient-derived organoids (PDOs), and mice. Mechanistically, removal of HDAC4 in FBXW7-mutated CRC treated with OXPT recreated an epigenetic state comparable to OXPT-sensitive cells. Furthermore, patient profiling based on the epigenetic state of the super-enhancers controlled by HDAC4 successfully identified a priori CRC patients resistant to platinum. This study supports HDAC4 as a key mediator of oxaliplatin resistance in FBXW7-mutated CRC and highlights the remodeling of a well-defined super-enhancer repertoire as part of the process of OXPT resensitization.

  PublisherOA PDFDOI

• Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling

  Journal of Clinical Investigation · 2025-06-15 · 2 citations

  articleOpen access

  Myxomatous valve disease (MVD) is the most common form of cardiac valve disease in the developed world. A small fraction of MVD is syndromic and arises in association with matrix protein defects such as those in Marfan syndrome, but most MVD is acquired later in life through an undefined pathogenesis. The KLF2/4 transcription factors mediate endothelial fluid shear responses, including those required to create cardiac valves during embryonic development. Here we test the role of hemodynamic shear forces and downstream endothelial KLF2/4 in mature cardiac valves. We find that loss of hemodynamic forces in heterotopically transplanted hearts or genetic deletion of KLF2/4 in cardiac valve endothelium confers valve cell proliferation and matrix deposition associated with valve thickening, findings also observed in mice expressing the mutant fibrillin-1 protein known to cause human MVD. Transcriptomic and histologic analysis reveals increased monocyte recruitment and TGF-β signaling in both fibrillin-1-mutant valves and valves lacking hemodynamic forces or endothelial KLF2/4 function, but only loss of TGF-β/SMAD signaling rescued myxomatous changes. We observed reduced KLF2/4 expression and augmented SMAD signaling in human MVD. These studies identify hemodynamic activation of endothelial KLF2/4 as an environmental homeostatic regulator of cardiac valves and suggest that non-syndromic MVD may arise in association with disturbed blood flow across the aging valve.

  PublisherDOI

• HDAC-6 Inhibition Provides Protection Against Acetaminophen-Induced Liver Injury

  American Journal of Transplantation · 2025-08-01

  articleOpen access
  PublisherOA PDFDOI

• Author response for "Class &lt;scp&gt;IIa HDACs&lt;/scp&gt; forced degradation allows resensitization of oxaliplatin‐resistant &lt;scp&gt;FBXW7&lt;/scp&gt; ‐mutated colorectal cancer"

  2025-09-17

  peer-review
  PublisherDOI

Recent grants

• NIH Grant R56AI095276

  NIH · $209k · 2013

• NIH Grant P01AI073489

  NIH · $14.1M · 2014

• NIH Grant R01CA158941

  NIH · $1.7M · 2016

• NIH Grant RC1DK087270

  NIH · $959k · 2012

• INHIBITION OF A TREG DEUBIQUITINASE, USP7, PROMOTES ANTI-TUMOR IMMUNITY

  NIH · $2.1M · 2015–2020

Frequent coauthors

• Liqing Wang

  Zhejiang Sci-Tech University

  308 shared

• Ulf H. Beier

  University of Pennsylvania

  167 shared

• Mohamed H. Sayegh

  University of Balamand

  164 shared

• Tatiana Akimova

  Children's Hospital of Philadelphia

  161 shared

• Rongxiang Han

  University of Pennsylvania

  129 shared

• Nicholas L. Tilney

  127 shared

• Matthew H. Levine

  University of Pennsylvania

  108 shared

• Fritz H. Bach

  Beth Israel Deaconess Medical Center

  97 shared

Education

• FRCPA

  Royal College of Pathologists of Australasia

  1989

• PhD, Medicine

  Monash University

  1983

• MB.BS, Medicine

  Monash University

  1977

Awards & honors

• F.R.C.P.A. (1984)
• Fellow, Royal College of Pathologists of Australasia (1989)