Victor H. Engelhard

Education

  • BA, Rice University, Houston, TX
  • MS, University of Illinois, Urbana, IL
  • PhD, University of Illinois, Urbana, IL
  • Postdoc, Harvard University, Cambridge, MA

Primary Appointment

  • Professor, Microbiology, Immunology, and Cancer Biology

Contact

Research Interest(s)

Identification of MHC-restricted tumor antigens / Control of T cell homing to tumors / Role of lymphatic endothelial cells in regulating immunity and self-tolerance

Research Description

Our research centers on understanding immune responses to tumors, and ways to enhance them for therapy. These responses depend on CD8 T lymphocytes, which recognize specific antigens on the tumor cell, leading to its destruction. Our work is in 3 areas. First, we identify antigens that tumor cells display. These antigens are small peptides produced by degradation of intracellular proteins, together with MHC molecules, which capture the peptides inside the cell and display them at the surface. Collaborating with Don Hunt in the Dept. of Chemistry, we developed mass spectrometry approaches to characterize the peptides displayed by MHC molecules. Recently, we identified phosphorylated peptides that are displayed on cancer cells, but not their normal counterparts. These peptides come from phosphoproteins associated with cellular signaling and growth control, and may be important targets for tumor immunotherapy. Many of these peptides are now in clinical trials at UVA as cancer vaccines. Second, we are pursuing the observation that many antigens on melanoma tumors are also on the normal cellular counterpart, the melanocyte. Immune responses against melanoma often lead to melanocyte destruction and autoimmune skin depigmentation. By using a transgenic mouse model, we have identified the mechanisms that establish self-tolerance to these antigens, but allow the persistence of cells that can recognize these melanoma/melanocyte antigens. We are trying to understand how the presence of tumors or vaccination alters self-tolerance, and the extent to which self-tolerance limits effective melanoma immunity. In the process, we have also discovered that lymph node stromal cells adventitiously express genes encoding antigens from other tissues, revealing a previously unknown mechanism of peripheral self-tolerance that we are investigating. Third, we are evaluating what controls the entry of T cells into tumors. A large fraction of tumors show no detectable lymphocyte infiltration, and these patients have a worse prognosis. We are discovering the molecules displayed on T cells, and their corresponding ligands on the tumor vasculature, to improve T cell infiltration as an important element of therapy.

Selected Publications

  • Peske J, Thompson E, Gemta L, Baylis R, Fu Y, Engelhard V. Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity. Nature communications. 2015;6 7114. PMID: 25968334 | PMCID: PMC4435831
  • Peske J, Woods A, Engelhard V. Control of CD8 T-Cell Infiltration into Tumors by Vasculature and Microenvironment. Advances in cancer research. 2015;128 263-307. PMID: 26216636 | PMCID: PMC4638417
  • Rouhani S, Eccles J, Riccardi P, Peske J, Tewalt E, Cohen J, Liblau R, Mäkinen T, Engelhard V. Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nature communications. 2015;6 6771. PMID: 25857745 | PMCID: PMC4403767
  • Rouhani S, Eccles J, Tewalt E, Engelhard V. Regulation of T-cell Tolerance by Lymphatic Endothelial Cells. Journal of clinical & cellular immunology. 2015;5. PMID: 25580369 | PMCID: PMC4286360
  • Cohen J, Tewalt E, Rouhani S, Buonomo E, Bruce A, Xu X, Bekiranov S, Fu Y, Engelhard V. Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment. PloS one. 2014;9(2): e87740. PMID: 24503860 | PMCID: PMC3913631
  • Zarling A, Obeng R, Desch A, Pinczewski J, Cummings K, Deacon D, Conaway M, Slingluff C, Engelhard V. MHC-restricted phosphopeptides derived from Insulin receptor substrate-2 and CDC25b offer broad-based immunotherapeutic agents for cancer. Cancer research. 2014. PMID: 25297629
  • Brinkman C, Peske J, Engelhard V. Peripheral tissue homing receptor control of naïve, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues. Frontiers in immunology. 2013;4 241. PMID: 23966998 | PMCID: PMC3746678
  • Brinkman C, Rouhani S, Srinivasan N, Engelhard V. Peripheral tissue homing receptors enable T cell entry into lymph nodes and affect the anatomical distribution of memory cells. Journal of immunology (Baltimore, Md. : 1950). 2013;191(5): 2412-25. PMID: 23926324 | PMCID: PMC3796582
  • Cobbold M, De La Peña H, Norris A, Polefrone J, Qian J, English A, Cummings K, Penny S, Turner J, Cottine J, Abelin J, Malaker S, Zarling A, Huang H, Goodyear O, Freeman S, Shabanowitz J, Pratt G, Craddock C, Williams M, Hunt D, Engelhard V. MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia. Science translational medicine. 2013;5(203): 203ra125. PMID: 24048523 | PMCID: PMC4071620
  • Engels B, Engelhard V, Sidney J, Sette A, Binder D, Liu R, Kranz D, Meredith S, Rowley D, Schreiber H. Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer cell. 2013;23(4): 516-26. PMID: 23597565 | PMCID: PMC3658176
  • Tewalt E, Cohen J, Rouhani S, Engelhard V. Lymphatic endothelial cells - key players in regulation of tolerance and immunity. Frontiers in immunology. 2012;3 305. PMID: 23060883 | PMCID: PMC3460259
  • Tewalt E, Cohen J, Rouhani S, Guidi C, Qiao H, Fahl S, Conaway M, Bender T, Tung K, Vella A, Adler A, Chen L, Engelhard V. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood. 2012. PMID: 22993390 | PMCID: PMC3520619
  • Cohen J, Guidi C, Tewalt E, Qiao H, Rouhani S, Ruddell A, Farr A, Tung K, Engelhard V. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. The Journal of experimental medicine. 2010;207(4): 681-8. PMID: 20308365 | PMCID: PMC2856027
  • Ferguson A, Engelhard V. CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors. Journal of immunology (Baltimore, Md. : 1950). 2010;184(8): 4079-86. PMID: 20212096 | PMCID: PMC2887738
  • Gregg R, Nichols L, Chen Y, Lu B, Engelhard V. Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice. Journal of immunology (Baltimore, Md. : 1950). 2010;184(4): 1909-17. PMID: 20083666 | PMCID: PMC2887735
  • Hulse K, Reefer A, Engelhard V, Patrie J, Ziegler S, Chapman M, Woodfolk J. Targeting allergen to FcgammaRI reveals a novel T(H)2 regulatory pathway linked to thymic stromal lymphopoietin receptor. The Journal of allergy and clinical immunology. 2010;125(1): 247-56.e1-8. PMID: 20109752 | PMCID: PMC2814452
  • Thompson E, Enriquez H, Fu Y, Engelhard V. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. The Journal of experimental medicine. 2010;207(8): 1791-804. PMID: 20660615 | PMCID: PMC2916130
  • Depontieu F, Qian J, Zarling A, McMiller T, Salay T, Norris A, English A, Shabanowitz J, Engelhard V, Hunt D, Topalian S. Identification of tumor-associated, MHC class II-restricted phosphopeptides as targets for immunotherapy. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(29): 12073-8. PMID: 19581576 | PMCID: PMC2715484
  • Ostankovitch M, Altrich-Vanlith M, Robila V, Engelhard V. N-glycosylation enhances presentation of a MHC class I-restricted epitope from tyrosinase. Journal of immunology (Baltimore, Md. : 1950). 2009;182(8): 4830-5. PMID: 19342661 | PMCID: PMC2859980
  • Tewalt E, Grant J, Granger E, Palmer D, Heuss N, Gregerson D, Restifo N, Norbury C. Viral sequestration of antigen subverts cross presentation to CD8(+) T cells. PLoS pathogens. 2009;5(5): e1000457. PMID: 19478869 | PMCID: PMC2680035
  • The contributions of mass spectrometry to understanding of immune recognition by T lymphocytes. International journal of mass spectrometry. 2008;259(1): 32-39. PMID: 18167512 | PMCID: PMC1920184
  • Brinkman C, Sheasley-O'Neill S, Ferguson A, Engelhard V. Activated CD8 T cells redistribute to antigen-free lymph nodes and exhibit effector and memory characteristics. Journal of immunology (Baltimore, Md. : 1950). 2008;181(3): 1814-24. PMID: 18641319 | PMCID: PMC2591092
  • Ferguson A, Nichols L, Zarling A, Thompson E, Brinkman C, Hargadon K, Bullock T, Engelhard V. Strategies and challenges in eliciting immunity to melanoma. Immunological reviews. 2008;222 28-42. PMID: 18363993 | PMCID: PMC2882710
  • Mohammed F, Cobbold M, Zarling A, Salim M, Barrett-Wilt G, Shabanowitz J, Hunt D, Engelhard V, Willcox B. Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self. Nature immunology. 2008;9(11): 1236-43. PMID: 18836451 | PMCID: PMC2596764
  • Robila V, Ostankovitch M, Altrich-Vanlith M, Theos A, Drover S, Marks M, Restifo N, Engelhard V. MHC class II presentation of gp100 epitopes in melanoma cells requires the function of conventional endosomes and is influenced by melanosomes. Journal of immunology (Baltimore, Md. : 1950). 2008;181(11): 7843-52. PMID: 19017974 | PMCID: PMC2659719
  • Tewalt E, Maynard J, Walters J, Schell A, Berwin B, Nicchitta C, Norbury C. Redundancy renders the glycoprotein 96 receptor scavenger receptor A dispensable for cross priming in vivo. Immunology. 2008;125(4): 480-91. PMID: 18489571 | PMCID: PMC2612544
  • Hunt D, Henderson R, Shabanowitz J, Sakaguchi K, Michel H, Sevilir N, Cox A, Appella E, Engelhard V. Pillars article: Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992. 255: 1261-1263. Journal of immunology (Baltimore, Md. : 1950). 2007;179(5): 2669-71. PMID: 17709476
  • Li L, Huang L, Sung S, Lobo P, Brown M, Gregg R, Engelhard V, Okusa M. NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. Journal of immunology (Baltimore, Md. : 1950). 2007;178(9): 5899-911. PMID: 17442974
  • Nichols L, Chen Y, Colella T, Bennett C, Clausen B, Engelhard V. Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes. Journal of immunology (Baltimore, Md. : 1950). 2007;179(2): 993-1003. PMID: 17617591
  • Reiley W, Jin W, Lee A, Wright A, Wu X, Tewalt E, Leonard T, Norbury C, Fitzpatrick L, Zhang M, Sun S. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. The Journal of experimental medicine. 2007;204(6): 1475-85. PMID: 17548520 | PMCID: PMC2118606
  • Sheasley-O'Neill S, Brinkman C, Ferguson A, Dispenza M, Engelhard V. Dendritic cell immunization route determines integrin expression and lymphoid and nonlymphoid tissue distribution of CD8 T cells. Journal of immunology (Baltimore, Md. : 1950). 2007;178(3): 1512-22. PMID: 17237400
  • Altrich-VanLith M, Ostankovitch M, Polefrone J, Mosse C, Shabanowitz J, Hunt D, Engelhard V. Processing of a class I-restricted epitope from tyrosinase requires peptide N-glycanase and the cooperative action of endoplasmic reticulum aminopeptidase 1 and cytosolic proteases. Journal of immunology (Baltimore, Md. : 1950). 2006;177(8): 5440-50. PMID: 17015730
  • Brickner A, Evans A, Mito J, Xuereb S, Feng X, Nishida T, Fairfull L, Ferrell R, Foon K, Hunt D, Shabanowitz J, Engelhard V, Riddell S, Warren E. The PANE1 gene encodes a novel human minor histocompatibility antigen that is selectively expressed in B-lymphoid cells and B-CLL. Blood. 2006;107(9): 3779-86. PMID: 16391015 | PMCID: PMC1895781
  • Donohue K, Grant J, Tewalt E, Palmer D, Theoret M, Restifo N, Norbury C. Cross-priming utilizes antigen not available to the direct presentation pathway. Immunology. 2006;119(1): 63-73. PMID: 16764686 | PMCID: PMC1782342
  • Hargadon K, Brinkman C, Sheasley-O'neill S, Nichols L, Bullock T, Engelhard V. Incomplete differentiation of antigen-specific CD8 T cells in tumor-draining lymph nodes. Journal of immunology (Baltimore, Md. : 1950). 2006;177(9): 6081-90. PMID: 17056534
  • Lappas C, Day Y, Marshall M, Engelhard V, Linden J. Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. The Journal of experimental medicine. 2006;203(12): 2639-48. PMID: 17088433 | PMCID: PMC2118143
  • Mullins D, Engelhard V. Limited infiltration of exogenous dendritic cells and naive T cells restricts immune responses in peripheral lymph nodes. Journal of immunology (Baltimore, Md. : 1950). 2006;176(8): 4535-42. PMID: 16585543
  • Norbury C, Tewalt E. Upstream toward the "DRiP"-ing source of the MHC class I pathway. Immunity. 2006;24(5): 503-6. PMID: 16713966
  • Slingluff C, Chianese-Bullock K, Bullock T, Grosh W, Mullins D, Nichols L, Olson W, Petroni G, Smolkin M, Engelhard V. Immunity to melanoma antigens: from self-tolerance to immunotherapy. Advances in immunology. 2006;90 243-95. PMID: 16730266
  • Slingluff C, Engelhard V, Ferrone S. Peptide and dendritic cell vaccines. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;12(7): 2342s-2345s. PMID: 16609056
  • Zarling A, Polefrone J, Evans A, Mikesh L, Shabanowitz J, Lewis S, Engelhard V, Hunt D. Identification of class I MHC-associated phosphopeptides as targets for cancer immunotherapy. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(40): 14889-94. PMID: 17001009 | PMCID: PMC1595446