Dario A.A. Vignali, Ph.D.
Campus: The Assembly, 5051 Centre Ave
Pittsburgh PA 15213
- BSc, Immunology and Medical Microbiology, North East London Polytechnic, 1985
- Ph.D., Immunology of Infectious Diseases, University of London, 1988
- Distinguished Professor and Interim Chair, Department of Immunology
- Frank Dixon Chair in Cancer Immunology
- Co-Leader of the Cancer Immunology & Immunotherapy Program
- Co-Director of the Cancer Immunology Training Program
- Scientific Director of Fondazione Ri.MED
- Associate Director for Scientific Strategy, UPMC Hillman Cancer Center
Our research focuses on various aspects of T cell regulation and function:
(1) Mechanistic Focus:
(a) Immune Regulation: Regulatory T cells (Tregs): Identification of novel Treg molecules and their function; mechanism of Treg function; regulation of Treg stability via Nrp1 and other pathways; IL-35 signaling and mechanism of action; novel Ebi3 binding partner; IL-10 & IFNy function; neuron-immune interactions.
(b) Immune Regulation: Inhibitory Molecules: Identification of novel inhibitory receptors (IR) and their mechanisms; immune modulation of T cell subsets by LAG3; PD1 and NRP1; PD1-LAG3 synergy; mechanism of CD8+ and CD4_ T cell exhaustion; protein engineering to develop novel therapeutics.
(c) Structure-function analysis of T cell receptor (TCR):CD3 complex and LAG3 signaling: Mechanism of TCR:CD3 signaling; modulation & control of TCR signaling by IRs.
(d) Systems Immunology: Single cell systems approaches (transcriptomic & epigenomic) to hypothesis test, hypthesis generate and discover; technology and algorithm development; multispectral imaging.
(2) Disease Focus:
(a) Cancer: Biology of LAG3/PD1, IL-35 and NRP1 in mouse models of cancer and also in samples from treatment-naive patients or immunotherapy recipients; primary focus on solid tumors – head & neck, melanoma, lung, ovarian, breast cancer, with some work on pancreatic, GI and glioma cancers, and pediatric solid malignancies; novel approaches for therapeutic translation; biomarker discovery.
(b) Autoimmune and Inflammatory Disease: Impact, function & insufficiency of Tregs and IRs in several autoimmune and inflammatory disease with emphasis on models of autoimmune diabetes (NOD), EAE and asthma; development of therapeutic approaches (enhance Treg stability; IR agonists.
Andrews LA, Vignali KM, Szymczak-Workman AL, Burton AR, Brunazzi EA, Ngiow SF, Harusato A, Sharpe AH, Wherry EJ, Taniuchi I, Workman CJ, Vignali DAA (2021). A Cre-driven allele-conditioning line to interrogate CD4+ conventional T cells. Immunity 54:2209-2217 [Free Article].
Chuckran CA, Cillo AR, Moskovitz J, Overacre-Delgoffe A, Somasundaram AS, Magnon GC, Abecassis I, Zureikat AH, Luketich J, Pennathur A, Sembrat J, Rojas M, Merrick DT, Taylor SE, Orr B, Modugno F, Bukanovich R, Schoen RE, Kim S, Duvvuri U, Zeh H, Edwards R, Kirkwood JM, Coffman L, Ferris RL, Bruno TC, Vignali DAA (2021). Neuropilin-1 Enforces Human Regulatory T cell Stability and Function in Solid Tumors. Science Translational Medicine 13:eabf8495 [PMCID: 9022491].
Andrews LP, Somasundaram A, Moskovitz JM, Szymczak-Workman AL, Liu C, Cillo AR, Lin H, Normolle DP, Moynihan KD, Taniuchi I, Irvine DJ, Kirkwood JM, Lipson EJ, Ferris RL, Bruno TC, Workman CJ, Vignali DAA (2020). Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding. Science Immunology 5:eabc2728 [PMCID: 7901539].
Cillo AR, Kürten C, Tabib T, Qi Z, Onkar S, Wang T, Liu L, Duvvuri U, Kim S, Soose RJ, Oesterreich S, Chen W, Lafyatis R, Bruno TC†, Ferris RL†, Vignali DAA† (2020). Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity 52:183-199 [PMCID: 7201194].
Liu C, Somasundaram A, Manne S, Gocher AM, Szymczak-Workman AL, Vignali KM, Scott EN, Normolle DP, Wherry EJ, Lipson EJ, Ferris RL, Bruno TC, Workman CJ, Vignali DAA (2020). Neuropilin-1 is a T cell memory checkpoint limiting long-term anti-tumor immunity. Nature Immunology 21:1010-1021 [PMCID: 7442600].
Sawant DV*, Yano H*, Chikina M, Zhang Q, Liao M, Liu C, Sun Z, Sun T, Tabib T, Pennathur A, Luketich JD, Lafyatis R, Chen W, Poholek A, Bruno TC, Workman CJ, Vignali DAA (2019). Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion. Nature Immunology 20:724-735 [PMCID: 6531353].
Liu C, Chikina M, Deshpande R, Menk AV, Wang T, Tabib T, Brunazzi EA, Vignali KM, Sun M, Stolz DB, Lafyatis RA, Chen W, Delgoffe GM, Workman CJ, Wendell SG, Vignali DAA (2019). Treg cells promote the SREBP1-dependent metabolic fitness of M2-like intratumoral macrophages via CD8+ T cells. Immunity 51:381-397 [PMCID: 6703933].
Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, Shuai Y, Normolle DP, Kirkwood J, Ferris RL, Delgoffe GM, Bruno TC, Workman CJ, Vignali DAA (2017). Interferon-g drives Treg fragility to promote anti-tumor immunity. Cell 169:1130-1141 [PMCID: 5509332].
Zhang Q, Chikina M, Szymczak-Workman AL, Horne W, Kolls JK, Vignali KM, Normolle D, Bettini M, Workman CJ, Vignali DAA (2017). LAG-3 limits regulatory T cell proliferation and function in autoimmune diabetes. Science Immunology 2:eaah4569 [PMCID: 5609824].
Turnis ME*, Sawant DV*, Szymczak-Workman A, Andrews LP, Delgoffe GM, Yano H, Beres AJ, Vogel P, Workman CJ, Vignali DAA (2016). Interleukin-35 limits anti-tumor immunity. Immunity 44: 316-329 [PMCID: 4758699].
Guy C, Vignali KM, Temirov J, Bettini ML, Overacre AE, Smeltzer M, Zhang H, Huppa JB, Tsai Y-H, Lobry C, Xie J, Dempsey PJ, Crawford HC, Aifantis I, Davis MM, Vignali DAA. Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nature Immunology 14:262-270, 2013. [Issue cover] [PMCID: 3577985].
Delgoffe GM*, Woo SR*, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J, Workman CJ, Vignali DAA. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 2013 Sep 12; 501(7466):252-256 [PMCID: 3867145].
Vignali DAA, Kurchroo VK (2012). IL-12 Family Cytokines: Immunlogical Playmakers. Nature Immunology 13: 722-728 [PMID: 22814351; PMCID: 4158817].
Collison LC*, Delgoffe GM*, Guy C, Vignali KM, Chaturvedi V, Fairweather D, Satoskar AR, Garcia KC, Hunter CA, Drake CG, Murray PJ, Vignali DAA (2012). The composition and signaling of the IL-35 receptor are unconventional. Nature Immunology 13: 290-299 [PMCID: 3529151].
Woo S-R*, Turnis ME*, Goldberg MV*, Bankoti J, Selby M, Nirschl CJ, Bettini ML, Vogel P, Liu C-L, Tangsombatvisit S, Grosso, JF, Netto G, Smeltzer MP, Chaux A, Utz PJ, Workman CJ, Pardoll DM, Korman AJ, Drake CG, Vignali DAA (2012). Immune inhibitory molecular LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Research 72: 917-927 [PMCID: 3288154].
Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, Finkelstein D, Forbes K, Workman CJ, Brown SA, Rehg JE, Jones ML, Ni H-T, Artis D, Turk MJ, Vignali DAA (2010). Interleukin-35-mediated induction of a potent regulatory T cell population. Nature Immunology 11: 1093-1101 [PMCID: 3008395].
Vignali DAA, Collison LW, Workman CJ (2008). How regulatory T cells work. Nature Reviews Immunology 8: 523-532 [PMID: 18566595; PMCID: 2665249].
Holst J, Wang H, Durick-Eder K, Workman CJ, Boyd K, Baquet Z, Singh H, Forbes K, Chruscinski A, Smeyne R, van Oers NSC, Utz PJ, Vignali DAA (2008). Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nature Immunology 9: 658-666 [PMID: 18469818].
Collison LW, Workman CJ, Kuo TK, BOyd K, Wang Y, Vignali K, Cross R, Sehy D, Blumberg RS, Vignali DAA (2007). The inhibitory cytokine IL-35 contributes to regulatory T cell function. Nature 450: 566-569 [PMID: 18033300].
Holst J, Vignali KM, Burton AR, Vignali DAA (2006). Rapid analysis of T cell selction and function in vivo using T cell receptor retrogenic mice. Nature Methods 3: 191-197 [PMID: 16489336].
Huang C-T, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Lavitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DAA (2004). Role of LAG-3 in regulatory T cellsw. Immunity 21: 503-13 [PMID: 15485628].
Szymczak AL, Workman CJ, Wang Y, Vignali KM, Dilioglou S, Vanin E, Vignali DAA (2004). Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector. Nature Biotechnology 22: 589-594 [PMID: 15064769].
- Our research focuses on gaining a better understanding of the inhibitory mechanisms, including inhibitory receptors and regulatory T cells, that limit anti-tumor immunity in cancer and are insufficient in autoimmune disease.
- We also have discovery-based programs aimed at identifying novel targets for therapeutic intervention.
- We are also working with UPMC Hillman Cancer Center scientists and clinicians to facilitate the translation of novel therapeutic modalities with a focus on immunologically impacted solid tumors (primarily head and neck, melanoma, lung, ovarian, breast).
- My UPMC Hillman Cancer Center leadership efforts, in part as co-leader of the Cancer Immunology & Immunotherapy Program, are directed toward providing a bridge between basic and transitional cancer immunology.
- We work extensively with large and start-up biopharmaceutical companies to bring novel therapeutics to the clinic.