Jonathan Duke-Cohan, Ph.D.

Medical Oncology/Hematologic Neoplasia

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Researcher

Principal Associate in Medicine, Harvard Medical School
Principal Research Scientist, DFCI

Contact Information

Office Phone Number617-632-3122

Bio

Dr. Duke-Cohan graduated from Queen Elizabeth College London in the UK and received his PhD from the Institute of Cancer Research (Chester Beatty Laboratories) of the University of London. Following postdoctoral work at the Ontario Cancer Institute in Toronto, he undertook a further postdoctoral then junior faculty position at the Lautenberg Center for Immunology and Cancer Research at the Hebrew University in Jerusalem, Israel. He joined the Dana-Farber Cancer Institute in 1989 to work in Prof. Stuart Schlossman’s Department until 2001. After completing a Barr Award in 2003, he joined the Laboratory of Immunobiology (Prof. Ellis Reinherz).

Recent Awards:

2016 – Visiting Professor (ongoing), Charles University, 1st Faculty of Medicine, Prague, Czech Republic
2001 – Claudia Adams Barr Award in Innovative Basic Cancer Research

Research

View Dr. Duke-Cohan's Research

Molecular and Cell Biological Investigations into Thymic Development
The development of the immune system designed to last a lifetime occurs in the thymus during our formative years. Early precursors from the bone marrow respond to chemokine signals to enter the thymus wherein they proliferate and develop as they weave through discrete environments in response to specific chemokines. Each successive environment provides the signals and nurturing conditions for selection of components of the T cell receptor TCR) that, under the best of circumstances, will lead to a mature repertoire eliminating or minimizing autoreactivity but maximizing the potential to respond to future infections or even respond to mutated proteins originating from cancer cells.
Our research is currently focused on the extracellular signals that influence selection of recombined TCR β chains for further development. Using molecular, cell biological and Next-Generation Sequencing (NGS) techniques, we follow the dynamics of individual recombined TCR β chain-bearing thymocytes and their subsequent survival into the periphery when combined with a particular TCR α chain. Once a particular αβTCR combination has been selected, the maturing thymocyte is required to move from the thymic cortex to the thymic medulla to undergo further selection processes. We showed that this translocation requires signaling by semaphorin 3E (sema3E) through thymocyte plexinD1 to release β1 integrin-mediated cortical adhesion. In defining the intracellular signaling pathway for the sema3E/plexinD1 interaction, we then demonstrated that the GTPase-activating protein Tagap, polymorphisms of which are already known to be strongly linked to autoimmune processes, is a non-redundant essential mediator for integrin release. We are now examining and defining the finer intricacies of this signaling pathway.
Insight into the developmental processes for selecting the TCR surviving into the mature T cell immune compartment has profound consequence not only for increasing our understanding of autoimmune pathologies but also for influencing or redirecting immune responses using modified recombinant proteins in vaccines.

View Dr. Duke-Cohan's Publications

Pre-T cell receptor self-MHC sampling restricts thymocyte dedifferentiation. Nature. 2023 01; 613(7944):565-574.
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Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease? Cancers (Basel). 2022 Apr 21; 14(9).
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TCR-mimic bispecific antibodies to target the HIV-1 reservoir. Proc Natl Acad Sci U S A. 2022 04 12; 119(15):e2123406119.
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Molecular design of the ?dT cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing. Proc Natl Acad Sci U S A. 2021 06 29; 118(26).
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Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity. Cancer Discov. 2021 08; 11(8):1952-1969.
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Pre-T cell receptors topologically sample self-ligands during thymocyte ß-selection. Science. 2021 01 08; 371(6525):181-185.
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Post-developmental extracellular proteoglycan maintenance in attractin-deficient mice. BMC Res Notes. 2020 Jun 24; 13(1):301.
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Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation. Commun Biol. 2020 03 17; 3(1):128.
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Cancer Neoepitopes for Immunotherapy: Discordance Between Tumor-Infiltrating T Cell Reactivity and Tumor MHC Peptidome Display. Front Immunol. 2019; 10:2766.
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NMR: an essential structural tool for integrative studies of T cell development, pMHC ligand recognition and TCR mechanobiology. J Biomol NMR. 2019 Jul; 73(6-7):319-332.
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Linking a mutation to survival in wild mice. Science. 2019 02 01; 363(6426):499-504.
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The T Cell Antigen Receptor a Transmembrane Domain Coordinates Triggering through Regulation of Bilayer Immersion and CD3 Subunit Associations. Immunity. 2018 11 20; 49(5):829-841.e6.
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Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity. Sci Signal. 2018 06 12; 11(534).
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Downregulation of semaphorin 3E promotes hallmarks of experimental chronic allergic asthma. Oncotarget. 2017 Nov 17; 8(58):98953-98963.
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Semaphorin 3E Alleviates Hallmarks of House Dust Mite-Induced Allergic Airway Disease. Am J Pathol. 2017 Jul; 187(7):1566-1576.
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Chemorepellent Semaphorin 3E Negatively Regulates Neutrophil Migration In Vitro and In Vivo. J Immunol. 2017 02 01; 198(3):1023-1033.
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Pre-T Cell Receptors (Pre-TCRs) Leverage Vß Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands. J Biol Chem. 2016 Dec 02; 291(49):25292-25305.
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Pre-TCR ligand binding impacts thymocyte development before aßTCR expression. Proc Natl Acad Sci U S A. 2015 Jul 07; 112(27):8373-8.
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RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med. 2014 May 05; 211(5):943-59.
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Dynamic control of ß1 integrin adhesion by the plexinD1-sema3E axis. Proc Natl Acad Sci U S A. 2014 Jan 07; 111(1):379-84.
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Plxnd1 expression in thymocytes regulates their intrathymic migration while that in thymic endothelium impacts medullary topology. Front Immunol. 2013; 4:392.
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CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. Cancer Immunol Immunother. 2013 Feb; 62(2):347-57.
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A coprecipitation-based validation methodology for interactions identified using protein microarrays. Methods Mol Biol. 2011; 723:239-54.
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Serologic markers of effective tumor immunity against chronic lymphocytic leukemia include nonmutated B-cell antigens. Cancer Res. 2010 Feb 15; 70(4):1344-55.
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Ethnic differences and functional analysis of MET mutations in lung cancer. Clin Cancer Res. 2009 Sep 15; 15(18):5714-23.
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p85 Associates with unphosphorylated PTEN and the PTEN-associated complex. Mol Cell Biol. 2009 Oct; 29(19):5377-88.
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Regulation of extracellular proteolysis by CUB-domain containing proteins. FEBS Journal. 2009; 276(Suppl. 1):18.

Immunogenicity of recombinant Modified Vaccinia Ankara following a single or multi-dose vaccine regimen in rhesus monkeys. Vaccine. 2009 Mar 04; 27(10):1549-56.
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The heterogeneity of human antibody responses to vaccinia virus revealed through use of focused protein arrays. Vaccine. 2009 Feb 18; 27(8):1154-65.
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PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla. Immunity. 2008 Dec 19; 29(6):888-98.
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Dipeptidyl peptidase-IV and related molecules: markers of malignancy? Expert Opin Med Diagn. 2008 Jun; 2(6):677-89.
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Dipeptidyl peptidase-IV and related molecules: markers of malignancy?. Expert Opinion on Medical Diagnostics. 2008; 6:1691-9.

Attractin, neurodegeneration and glioma development. Tumor Biology. 2007; 28(Supplement 1):3.

Genetic fixity in the human major histocompatibility complex and block size diversity in the class I region including HLA-E. BMC Genet. 2007 Apr 12; 8:14.
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Juvenile-onset loss of lipid-raft domains in attractin-deficient mice. Exp Cell Res. 2007 Feb 15; 313(4):761-71.
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Attractin is elevated in the cerebrospinal fluid of patients with malignant astrocytoma and mediates glioma cell migration. Clin Cancer Res. 2006 Nov 01; 12(21):6331-6.
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Siva-1 negatively regulates NF-kappaB activity: effect on T-cell receptor-mediated activation-induced cell death (AICD). Oncogene. 2006 Jun 08; 25(24):3458-62.
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Regulation and function of SKAP-55 non-canonical motif binding to the SH3c domain of adhesion and degranulation-promoting adaptor protein. J Biol Chem. 2006 May 12; 281(19):13743-13750.
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Dipeptidyl peptidase IV activity and/or structure homologs: contributing factors in the pathogenesis of rheumatoid arthritis? Arthritis Res Ther. 2005; 7(6):253-69.
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