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Engelhard, Victor

Victor Engelhard

Primary Appointment

Microbiology, Immunology, and Cancer Biology

Contact Information

Carter Immunology Center
Charlottesville, Virginia 22908
Telephone: 434-924-2423
Fax: 434-924-1221
Email: vhe@virginia.edu

Research Interests

Identification of MHC-restricted tumor antigens / Control of T cell homing to tumors / Tertiary lymphoid structures and intratumoral immunity

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 major areas. First, we identify antigens that tumor cells display. These antigens are small peptides produced by degradation of intracellular proteins, which are then captured by MHC molecules and displayed at the surface. Recently, we showed that some of these peptides are phosphorylated, and 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. Some of these peptides are now in clinical trials at UVA as cancer vaccines. Second, we are evaluating the mechanisms that control the entry of CD8 T cells into tumors. A large fraction of tumors shows no detectable lymphocyte infiltration, and these patients have a worse prognosis. We identified the homing receptors that are upregulated on effector CD8 T cells activated in different secondary lymphoid organs, and established their importance in mediated entry of these cells into tumors. We also identified the homing receptor ligands expressed on tumor-associated vasculature and established that their expression is suboptimal. Current work is concerned with understanding the mechanisms that control their expression as a means to enhance T cell infiltration and tumor control. Finally, we have established that parts of tumor associated vasculature express molecules characteristic of lymph node vasculature. This leads to the infiltration and intratumoral activation of na?ve T cells, and can also lead to the formation of structures resembling lymph nodes inside the tumor. We are determining the importance of these structures in developing an ongoing intratumoral immune response that would augment control of tumor growth.

Selected Publications

Leick KM, Rodriguez AB, Melssen MM, Benamar M, Lindsay RS, Eki R, Du KP, Parlak M, Abbas T, Engelhard VH, Slingluff CL, The Barrier Molecules Junction Plakoglobin, Filaggrin, and Dystonin Play Roles in Melanoma Growth and Angiogenesis., 2019; Annals of surgery. 270(4) 712-722 PMID: 31425296 |

Leick KM, Pinczewski J, Mauldin IS, Young SJ, Deacon DH, Woods AN, Bosenberg MW, Engelhard VH, Slingluff CL, Patterns of immune-cell infiltration in murine models of melanoma: roles of antigen and tissue site in creating inflamed tumors., 2019; Cancer immunology, immunotherapy : CII. 68(7) 1121-1132 PMID: 31134297 |

Santambrogio L, Berendam SJ, Engelhard VH, The Antigen Processing and Presentation Machinery in Lymphatic Endothelial Cells., 2019; Frontiers in immunology. 10() 1033 PMID: 31134089 | PMCID: PMC6513971

Berendam SJ, Koeppel AF, Godfrey NR, Rouhani SJ, Woods AN, Rodriguez AB, Peske JD, Cummings KL, Turner SD, Engelhard VH, Comparative Transcriptomic Analysis Identifies a Range of Immunologically Related Functional Elaborations of Lymph Node Associated Lymphatic and Blood Endothelial Cells., 2019; Frontiers in immunology. 10() 816 PMID: 31057546 | PMCID: PMC6478037

Melssen MM, Olson W, Wages NA, Capaldo BJ, Mauldin IS, Mahmutovic A, Hutchison C, Melief CJM, Bullock TN, Engelhard VH, Slingluff CL, Formation and phenotypic characterization of CD49a, CD49b and CD103 expressing CD8 T cell populations in human metastatic melanoma., 2018; Oncoimmunology. 7(10) e1490855 PMID: 30288359 | PMCID: PMC6169593

Rodriguez AB, Peske JD, Engelhard VH, Identification and Characterization of Tertiary Lymphoid Structures in Murine Melanoma., 2018; Methods in molecular biology (Clifton, N.J.). 1845() 241-257 PMID: 30141017 | PMCID: PMC6269110

Hailemichael Y, Woods A, Fu T, He Q, Nielsen MC, Hasan F, Roszik J, Xiao Z, Vianden C, Khong H, Singh M, Sharma M, Faak F, Moore D, Dai Z, Anthony SM, Schluns KS, Sharma P, Engelhard VH, Overwijk WW, Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy., 2018; The Journal of clinical investigation. 128(4) 1338-1354 PMID: 29480817 | PMCID: PMC5873868

Engelhard VH, Rodriguez AB, Mauldin IS, Woods AN, Peske JD, Slingluff CL, Immune Cell Infiltration and Tertiary Lymphoid Structures as Determinants of Antitumor Immunity., 2018; Journal of immunology (Baltimore, Md. : 1950). 200(2) 432-442 PMID: 29311385 | PMCID: PMC5777336

Woods AN, Wilson AL, Srivinisan N, Zeng J, Dutta AB, Peske JD, Tewalt EF, Gregg RK, Ferguson AR, Engelhard VH, Differential Expression of Homing Receptor Ligands on Tumor-Associated Vasculature that Control CD8 Effector T-cell Entry., 2017; Cancer immunology research. 5(12) 1062-1073 PMID: 29097419 | PMCID: PMC6069521

Mohammed F, Stones DH, Zarling AL, Willcox CR, Shabanowitz J, Cummings KL, Hunt DF, Cobbold M, Engelhard VH, Willcox BE, The antigenic identity of human class I MHC phosphopeptides is critically dependent upon phosphorylation status., 2017; Oncotarget. 8(33) 54160-54172 PMID: 28903331 | PMCID: PMC5589570

Malaker SA, Ferracane MJ, Depontieu FR, Zarling AL, Shabanowitz J, Bai DL, Topalian SL, Engelhard VH, Hunt DF, Identification and Characterization of Complex Glycosylated Peptides Presented by the MHC Class II Processing Pathway in Melanoma., 2016; Journal of proteome research. 16(1) 228-237 PMID: 27550523 | PMCID: PMC5218890

Peske JD, Thompson ED, Gemta L, Baylis RA, Fu YX, Engelhard VH, Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity., 2015; Nature communications. 6() 7114 PMID: 25968334 | PMCID: PMC4435831

Rouhani SJ, Eccles JD, Riccardi P, Peske JD, Tewalt EF, Cohen JN, Liblau R, M?kinen T, Engelhard VH, Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction., 2015; Nature communications. 6() 6771 PMID: 25857745 | PMCID: PMC4403767

Rouhani SJ, Eccles JD, Tewalt EF, Engelhard VH, Regulation of T-cell Tolerance by Lymphatic Endothelial Cells., 2015; Journal of clinical & cellular immunology. 5() PMID: 25580369 | PMCID: PMC4286360

Peske JD, Woods AB, Engelhard VH, Control of CD8 T-Cell Infiltration into Tumors by Vasculature and Microenvironment., 2015; Advances in cancer research. 128() 263-307 PMID: 26216636 | PMCID: PMC4638417

Cohen JN, Tewalt EF, Rouhani SJ, Buonomo EL, Bruce AN, Xu X, Bekiranov S, Fu YX, Engelhard VH, Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment., 2014; PloS one. 9(2) e87740 PMID: 24503860 | PMCID: PMC3913631

Zarling AL, Obeng RC, Desch AN, Pinczewski J, Cummings KL, Deacon DH, Conaway MR, Slingluff C, Engelhard VH, MHC-restricted phosphopeptides derived from Insulin receptor substrate-2 and CDC25b offer broad-based immunotherapeutic agents for cancer., 2014; Cancer research. () PMID: 25297629 |

Brinkman CC, Rouhani SJ, Srinivasan N, Engelhard VH, Peripheral tissue homing receptors enable T cell entry into lymph nodes and affect the anatomical distribution of memory cells., 2013; Journal of immunology (Baltimore, Md. : 1950). 191(5) 2412-25 PMID: 23926324 | PMCID: PMC3796582

Engels B, Engelhard VH, Sidney J, Sette A, Binder DC, Liu RB, Kranz DM, Meredith SC, Rowley DA, Schreiber H, Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity., 2013; Cancer cell. 23(4) 516-26 PMID: 23597565 | PMCID: PMC3658176

Cobbold M, De La Pe?a H, Norris A, Polefrone JM, Qian J, English AM, Cummings KL, Penny S, Turner JE, Cottine J, Abelin JG, Malaker SA, Zarling AL, Huang HW, Goodyear O, Freeman SD, Shabanowitz J, Pratt G, Craddock C, Williams ME, Hunt DF, Engelha..., MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia., 2013; Science translational medicine. 5(203) 203ra125 PMID: 24048523 | PMCID: PMC4071620

Brinkman CC, Peske JD, Engelhard VH, Peripheral tissue homing receptor control of na?ve, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues., 2013; Frontiers in immunology. 4() 241 PMID: 23966998 | PMCID: PMC3746678

Tewalt EF, Cohen JN, Rouhani SJ, Guidi CJ, Qiao H, Fahl SP, Conaway MR, Bender TP, Tung KS, Vella AT, Adler AJ, Chen L, Engelhard VH, Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells., 2012; Blood. () PMID: 22993390 | PMCID: PMC3520619

Tewalt EF, Cohen JN, Rouhani SJ, Engelhard VH, Lymphatic endothelial cells - key players in regulation of tolerance and immunity., 2012; Frontiers in immunology. 3() 305 PMID: 23060883 | PMCID: PMC3460259

Thompson ED, Enriquez HL, Fu YX, Engelhard VH, Tumor masses support naive T cell infiltration, activation, and differentiation into effectors., 2010; The Journal of experimental medicine. 207(8) 1791-804 PMID: 20660615 | PMCID: PMC2916130

Li Y, Depontieu FR, Sidney J, Salay TM, Engelhard VH, Hunt DF, Sette A, Topalian SL, Mariuzza RA, Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells., 2010; Journal of molecular biology. 399(4) 596-603 PMID: 20417641 | PMCID: PMC2904831

Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, Farr AG, Tung KS, Engelhard VH, Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation., 2010; The Journal of experimental medicine. 207(4) 681-8 PMID: 20308365 | PMCID: PMC2856027

Ferguson AR, Engelhard VH, CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors., 2010; Journal of immunology (Baltimore, Md. : 1950). 184(8) 4079-86 PMID: 20212096 | PMCID: PMC2887738

Gregg RK, Nichols L, Chen Y, Lu B, Engelhard VH, Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice., 2010; Journal of immunology (Baltimore, Md. : 1950). 184(4) 1909-17 PMID: 20083666 | PMCID: PMC2887735

Nicholls S, Piper KP, Mohammed F, Dafforn TR, Tenzer S, Salim M, Mahendra P, Craddock C, van Endert P, Schild H, Cobbold M, Engelhard VH, Moss PA, Willcox BE, Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition., 2009; Proceedings of the National Academy of Sciences of the United States of America. 106(10) 3889-94 PMID: 19234124 | PMCID: PMC2656175

Depontieu FR, Qian J, Zarling AL, McMiller TL, Salay TM, Norris A, English AM, Shabanowitz J, Engelhard VH, Hunt DF, Topalian SL, Identification of tumor-associated, MHC class II-restricted phosphopeptides as targets for immunotherapy., 2009; Proceedings of the National Academy of Sciences of the United States of America. 106(29) 12073-8 PMID: 19581576 | PMCID: PMC2715484

Ostankovitch M, Altrich-Vanlith M, Robila V, Engelhard VH, N-glycosylation enhances presentation of a MHC class I-restricted epitope from tyrosinase., 2009; Journal of immunology (Baltimore, Md. : 1950). 182(8) 4830-5 PMID: 19342661 | PMCID: PMC2859980

Tewalt EF, Grant JM, Granger EL, Palmer DC, Heuss ND, Gregerson DS, Restifo NP, Norbury CC, Viral sequestration of antigen subverts cross presentation to CD8(+) T cells., 2009; PLoS pathogens. 5(5) e1000457 PMID: 19478869 | PMCID: PMC2680035

Robila V, Ostankovitch M, Altrich-Vanlith ML, Theos AC, Drover S, Marks MS, Restifo N, Engelhard VH, MHC class II presentation of gp100 epitopes in melanoma cells requires the function of conventional endosomes and is influenced by melanosomes., 2008; Journal of immunology (Baltimore, Md. : 1950). 181(11) 7843-52 PMID: 19017974 | PMCID: PMC2659719

Mohammed F, Cobbold M, Zarling AL, Salim M, Barrett-Wilt GA, Shabanowitz J, Hunt DF, Engelhard VH, Willcox BE, Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self., 2008; Nature immunology. 9(11) 1236-43 PMID: 18836451 | PMCID: PMC2596764

Tewalt EF, Maynard JC, Walters JJ, Schell AM, Berwin BL, Nicchitta CV, Norbury CC, Redundancy renders the glycoprotein 96 receptor scavenger receptor A dispensable for cross priming in vivo., 2008; Immunology. 125(4) 480-91 PMID: 18489571 | PMCID: PMC2612544

Brinkman CC, Sheasley-O'Neill SL, Ferguson AR, Engelhard VH, Activated CD8 T cells redistribute to antigen-free lymph nodes and exhibit effector and memory characteristics., 2008; Journal of immunology (Baltimore, Md. : 1950). 181(3) 1814-24 PMID: 18641319 | PMCID: PMC2591092

Ferguson AR, Nichols LA, Zarling AL, Thompson ED, Brinkman CC, Hargadon KM, Bullock TN, Engelhard VH, Strategies and challenges in eliciting immunity to melanoma., 2008; Immunological reviews. 222() 28-42 PMID: 18363993 | PMCID: PMC2882710

Engelhard VH, The contributions of mass spectrometry to understanding of immune recognition by T lymphocytes., 2008; International journal of mass spectrometry. 259(1) 32-39 PMID: 18167512 | PMCID: PMC1920184

Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF, Leonard TO, Norbury CC, Fitzpatrick L, Zhang M, Sun SC, Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses., 2007; The Journal of experimental medicine. 204(6) 1475-85 PMID: 17548520 | PMCID: PMC2118606

Hunt DF, Henderson RA, Shabanowitz J, Sakaguchi K, Michel H, Sevilir N, Cox AL, Appella E, Engelhard VH, Pillars article: Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992. 255: 1261-1263., 2007; Journal of immunology (Baltimore, Md. : 1950). 179(5) 2669-71 PMID: 17709476 |

Nichols LA, Chen Y, Colella TA, Bennett CL, Clausen BE, Engelhard VH, Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes., 2007; Journal of immunology (Baltimore, Md. : 1950). 179(2) 993-1003 PMID: 17617591 |

Sheasley-O'Neill SL, Brinkman CC, Ferguson AR, Dispenza MC, Engelhard VH, Dendritic cell immunization route determines integrin expression and lymphoid and nonlymphoid tissue distribution of CD8 T cells., 2007; Journal of immunology (Baltimore, Md. : 1950). 178(3) 1512-22 PMID: 17237400 |

Li L, Huang L, Sung SS, Lobo PI, Brown MG, Gregg RK, Engelhard VH, Okusa MD, NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury., 2007; Journal of immunology (Baltimore, Md. : 1950). 178(9) 5899-911 PMID: 17442974 |

Hargadon KM, Brinkman CC, Sheasley-O'neill SL, Nichols LA, Bullock TN, Engelhard VH, Incomplete differentiation of antigen-specific CD8 T cells in tumor-draining lymph nodes., 2006; Journal of immunology (Baltimore, Md. : 1950). 177(9) 6081-90 PMID: 17056534 |

Zarling AL, Polefrone JM, Evans AM, Mikesh LM, Shabanowitz J, Lewis ST, Engelhard VH, Hunt DF, Identification of class I MHC-associated phosphopeptides as targets for cancer immunotherapy., 2006; Proceedings of the National Academy of Sciences of the United States of America. 103(40) 14889-94 PMID: 17001009 | PMCID: PMC1595446

Altrich-VanLith ML, Ostankovitch M, Polefrone JM, Mosse CA, Shabanowitz J, Hunt DF, Engelhard VH, 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., 2006; Journal of immunology (Baltimore, Md. : 1950). 177(8) 5440-50 PMID: 17015730 |

Brickner AG, Evans AM, Mito JK, Xuereb SM, Feng X, Nishida T, Fairfull L, Ferrell RE, Foon KA, Hunt DF, Shabanowitz J, Engelhard VH, Riddell SR, Warren EH, The PANE1 gene encodes a novel human minor histocompatibility antigen that is selectively expressed in B-lymphoid cells and B-CLL., 2006; Blood. 107(9) 3779-86 PMID: 16391015 | PMCID: PMC1895781

Mullins DW, Engelhard VH, Limited infiltration of exogenous dendritic cells and naive T cells restricts immune responses in peripheral lymph nodes., 2006; Journal of immunology (Baltimore, Md. : 1950). 176(8) 4535-42 PMID: 16585543 |

Slingluff CL, Engelhard VH, Ferrone S, Peptide and dendritic cell vaccines., 2006; Clinical cancer research : an official journal of the American Association for Cancer Research. 12(7) 2342s-2345s PMID: 16609056 |

Slingluff CL, Chianese-Bullock KA, Bullock TN, Grosh WW, Mullins DW, Nichols L, Olson W, Petroni G, Smolkin M, Engelhard VH, Immunity to melanoma antigens: from self-tolerance to immunotherapy., 2006; Advances in immunology. 90() 243-95 PMID: 16730266 |

Donohue KB, Grant JM, Tewalt EF, Palmer DC, Theoret MR, Restifo NP, Norbury CC, Cross-priming utilizes antigen not available to the direct presentation pathway., 2006; Immunology. 119(1) 63-73 PMID: 16764686 | PMCID: PMC1782342

Norbury CC, Tewalt EF, Upstream toward the "DRiP"-ing source of the MHC class I pathway., 2006; Immunity. 24(5) 503-6 PMID: 16713966 |

Lappas CM, Day YJ, Marshall MA, Engelhard VH, Linden J, Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation., 2006; The Journal of experimental medicine. 203(12) 2639-48 PMID: 17088433 | PMCID: PMC2118143