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)

Immune responses to tumors and immunotherapy / Impact of self-tolerance on anti-tumor immunity / Processing and presentation of MHC-restricted antigens

Research Description

Our research centers on understanding immune responses to tumors, and defining ways to enhance it for therapeutic purposes. Work by our lab and other has established that these immune responses are usually dependent on CD8 T lymphocytes, which recognize specific antigens displayed on the surface of the tumor cells. This recognition leads to the direct destruction of tumor cells, or enhances the overall inflammatory environment within the tumor to cause destruction by other mechanisms. Within this framework, our work is focused in 3 areas.

First, we are engaged in identifying the antigens that tumor cells display, and that can be recognized by CD8 T lymphocytes. These antigens are created from two parts: small peptides, produced by the degradation of intracellular proteins, and proteins called MHC molecules, which capture these peptides inside the cell and display them at the cell surface. In collaboration with Dr. Donald Hunt in the Dept. of Chemistry and Dr. Craig Slingluff in the Dept of Surgery, we have developed mass spectrometry approaches for characterizing the complex mixture of peptides displayed by MHC molecules, and have defined a subset that are recognized by T cells during immune reactions to human melanoma tumor cells. Most recently, we have identified a set of phosphorylated peptides that are displayed on cancer cells, but not their normal counterparts. These peptides are derived from phosphoproteins associated with cellular signaling and transformation, suggesting that they may be particularly important targets for tumor immunotherapy. Many of the peptides we have identified are now being used in clinical trials at UVA to develop therapeutic vaccines for melanoma. Second, we are using transgenic mice that express human MHC molecules to model the human immune response to melanoma. This unique “preclinical” model is being used to systematically understand the quality of the response, the reasons that it ultimately fails to control melanoma, and to design and evaluate approaches to enhance effective immunity. The insights gained from this work can be used to accelerate progress in human clinical trials by identifying more useful approaches more rapidly than would otherwise be possible. Third, we are pursuing the intriguing observation that many of the antigens recognized on melanoma tumors by T lymphocytes are also expressed on the tumor's normal cellular counterpart, the melanocyte. Indeed, immune responses against melanoma often lead to autoimmune skin depigmentation. Again, by using a transgenic mouse model, we are evaluating the mechanisms that establish self-tolerance to these antigens, and which nonetheless allow the persistence of cells that can recognize these melanoma/melanocyte antigens. In conjunction with this, we are trying to understand how the presence of melanoma tumors or vaccination alters the occurrence of self-tolerance, and the extent to which self-tolerance still limits effective melanoma immunity. This model allows us to evaluate the existence and impact of self-tolerance on effective anti-melanoma immune responses.

Selected Publications

  • 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
  • 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
  • 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
  • Rival C, Wheeler K, Jeffrey S, Qiao H, Luu B, Tewalt E, Engelhard V, Tardif S, Hardy D, del Rio R, Teuscher C, Tung K. Regulatory T cells and vasectomy. Journal of reproductive immunology. 2013;100(1): 66-75. PMID: 24080233 | PMCID: PMC3965253
  • 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
  • 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