Dhifaf Sarhan

About me

Sarhan was recruited to the Department of Microbiology, Tumor and Cell biology as Assistant Professor in Tumor immunology/Immunotherapy in 2019 and as group leader at LABMED/Division of Pathology in 2021. Sarhan completed her Ph.D. at the Department of Oncology-Pathology, Karolinska Institutet in 2014 followed by a postdoctoral training at the University of Minnesota. The group research interest focuses on studying the consequences of the tumor microenvironment (TME) on shaping the immune effector cell function and memory aiming to remodel the TME to improved cancer immunotherapies in a sex-dependent manner.

Research description

Project I: Adaptive NK cell immunological memory in cancer

For decades NK cells were believed to lack the immunological memory, however recent groundbreaking research by us and others revealed the opposite. We discovered novel mechanisms used by a subset of NK cells with immunological memory, called adaptive NK cells, to resist the suppressive tumor environment. In this project we focus on investigating the molecular mechanisms behind NK cell memory to tumors and the crosstalk with antigen presenting cells like dendritic cells and B cells in cancer. 

 

Project II: Targeting of suppressive myeloid cells for cancer immunotherapy

The goal for this project is to identify specific targets for tumor-associated macrophages and myeloid-derived suppresor cells to reprogram their suppressive nature and later develop target antibodies to relieve the anti-tumor activity of Natural Killer (NK) cells and T cells. Currently we are studying g-coupled protein receptors as therapeutic targets in GI-tract cancers. 

 

Project III: Study the mechanisms of immune exclusion in GI-tract tumors highly infiltrated by myeloid cells

In this project, we study the myeloid cell-dependent inhibitory mechanisms of NK and T cell infiltration into cold and immune excluded GI-tract tumors. Patient tumor and blood specimens are provided by national and international collaborators. Further, we are extensively examining the receptor signal integration in suppressive myeloid cells.

 

Project IV: Studies of sexual dimorphism in the TME

We found that a G-protein coupled receptor has predictive value for female cancer patients and induce immune cell exhaustion. Hormone regulation of this receptor function has been shown to induce anti-inflammatory properties in macrophages.This receptor impacts the immune landscape in pancreatic cancer TME biased by sex dimorphism. Extensive examination of the signal integration is needed to further elucidate its mechanism of action and clinical impact.

 

Lab members:

Dhifaf Sarhan, Group leader

Lena Hernberg, Lab manager

Fei He, PhD student

Nerea Martín Almazán, PhD student

Yizhe Sun, PhD student

Cassandra Sterner, student

Charlotte Herman, Erasmus master student

 

Alumni:

Andrea Rodgers Furones, Erasmus Trainee/master student

Marina Kaisso, Master student

Enana Malki, Master student 

Ahmed Husseini, Master thesis

Catarina Pelicano, Erasmus internship programme

Mariana Alcocer Bonifaz, Master thesis project

Martin Borgmann, Erasmus internship programme

Suborna Mastafa, Bachelor thesis project

Caroline Driescher, Master thesis project

 

 

Teaching portfolio

Teaching in immunology and tumor immunology at Karolinska Institutet and Uppsala University.

Education

2010-2014: PhD, Dept. of Oncology-Pathology, Karolinska Institutet (KI), Sweden.

2008-2010: M.S, Biomedicine, Karolinska Institutet, Stockholm, Sweden

2005-2008: B.S Molecular biology, Uppsala University, Uppsala, Sweden

Academic honours, awards and prizes

Junior Investigator Award, Swedish Cancer Society

Jonas Söderquist's scholarship

Selected for 3-years CANCER CORE EUROPE advanced training program TRYTRAC in translational/clinical research and leadership

World Immunotherapy Council, Young Investigator Award

Best abstract, Cancer immunotherapy and immunomonitoring (CITIM)

Pancreatic cancer fellow, Swedish Cancer Society

Postdoctoral fellowship, Karolinska Institutet and University of Minnesota, Minneapolis, Minnesota USA

Award for research-project, ImmunoTools

Scholarship, Swedish Order of Freemasons

 

Funding

Current

Centrum for innovative medicine

Swedish Cancer Society

Stiftelsen Clas Groschinsky Minnesfonds

Jonas Söderquist foundation

KI Stiftelser och Fonder

Stiftelsen Sigurd and Elsa Goljes Minne

The Sjöberg foundation

 

Past

Postdoctoral fellowship Karolinska Institutet, University of Minnesota

Novo, NovoSeeds

Robert Lundbergs minnesstiftelse

 

Publication

Original articles

Gultekin O, Gonzalez-Molina J, Hardell E, Moyano-Galceran L, Mitsios N, Mulder J, Kokaraki G, Isaksson A, Sarhan D, Kaisa Lehti, Carlson J. FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation. NPJPRECISIONONCOLOGY, 2021.

Chen Z, Yang Y, Neo S, Shi H, Mr. Chen Y, Wagner A, Larsson K, Jakobsson PJ, Wang K, Prof. Alici E, Wu J, Cao Y,  Mao Y, Sarhan D, Lundqvist A. Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25+/CD54+ NK cells. EMBO Reports, 2021.

Evren E, Ringqvist E, Tripathi KP, Sleiers N, Rives IC, Alisjahbana A, Gao Y, Sarhan D, Halle T, Sorini C, Lepzien R, Marquardt N, Michaëlsson J, Smed-Sörensen A, Botling J, Karlsson MCI, Villablanca EJ, Willinger T. Distinct developmental pathways from blood monocytes generate human lung macrophage diversity. Immunity. 2020

La Fleur L, Botling J, He F, Pelicano C, Zhou C, He C, Palano G, Mezheyeuski A, Micke P, Ravetch JV, Karlsson MCI, Sarhan D. Targeting MARCO and IL-37R on immunosuppressive macrophages in lung cancer blocks regulatory T cells and supports cytotoxic lymphocyte function. Cancer Res. 2020

Eisinger S, Sarhan D, Boura VF, Ibarlucea-Benitez I, Tyystjärvi S, Oliynyk G, Arsenian-Henriksson M, Lane D, Wikström SL, Kiessling R, Virgilio T, Gonzalez SF, Kaczynska D, Kanatani S, Daskalaki E, Wheelock CE, Sedimbi S, Chambers BJ, Ravetch JV, Karlsson MCI. Targeting a scavenger receptor on tumor-associated macrophages activates tumor cell killing by natural killer cells. PNAS. 2020

Sarhan D, Wang J, Sunil Arvindam U, Hallstrom C, Verneris MR, Grzywacz B, Warlick E, Blazar BR, Miller JS. Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell function. JCI Insight. 2020

Sarhan D, Brandt L, Felices M, Guldevall K, Lenvik T, Hinderlie P, Curtsinger J, Warlick E, Spellman SR, Blazar BR, Weisdorf DJ, Cooley S, Vallera DA, Önfelt B, Miller JS. 161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. Blood Adv. 2018

Sarhan D, Hippen KL, Lemire A, Hying S, Luo X, Lenvik T, Curtsinger J, Davis Z, Zhang B, Cooley S, Cichocki F, Blazar BR, Miller JS. Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37. Cancer Immunol Res. 2018

de Witte MA, Sarhan D, Davis Z, Felices M, Vallera DA, Hinderlie P, Curtsinger J, Cooley S, Wagner J, Kuball J, Miller JS. Early Reconstitution of NK and γδ T Cells and Its Implication for the Design of Post-Transplant Immunotherapy. Biol Blood Marrow Transplant, 2018. 

Bachanova V, Sarhan D, DeFor TE, Cooley S, Panoskaltsis-Mortari A, Blazar BR, Curtsinger JM, Burns L, Weisdorf DJ, Miller JS. Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells. Cancer immunology,immunotherapy : CII 2018 67;3 483-494

Sarhan D*, Leijonhufvud C*, Murray S, Witt K, Seitz C, Wallerius M, Xie HJ, Ullen A, Harmenberg U, Lidbrink E, Rolny C, Andersson J, Lundqvist A. Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer. ONCOIMMUNOLOGY 2017 6;8 e1338238-

Cichocki F, Valamehr B, Bjordahl R, Zhang B, Rezner B, Rogers P, Gaidarova S, Moreno S, Tuininga K, Dougherty P, McCullar V, Howard P, Sarhan D, Taras E, Schlums H, Abbot S, Shoemaker D, Bryceson YT, Blazar BR, Wolchko S, Cooley S, Miller JS. GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity. Cancer research 2017 77;20 5664-5675

Lövgren T, Sarhan D, Truxová I, Choudhary B, Maas R, Melief J, Nyström M, Edbäck U, Vermeij R, Scurti G, Nishimura M, Masucci G, Karlsson-Parra A, Lundqvist A, Adamson L, Kiessling R. Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists. Cancer immunology, immunotherapy: CII 2017 66;10 1333-1344

Luu TT, Ganesan S, Wagner AK, Sarhan D, Meinke S, Garbi N, Hämmerling G, Alici E, Kärre K, Chambers BJ, Höglund P, Kadri N. Independent control of natural killer cell responsiveness and homeostasis at steady-state by CD11c+ dendritic cells. Scientific reports 2016 6; 37996-

Sarhan D, Cichocki F, Zhang B, Yingst A, Spellman SR, Cooley S, Verneris MR, Blazar BR, Miller JS. Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells. CANCER RESEARCH 2016 76;19 5696-5706

Sarhan D, Palma M, Mao Y, Adamson L, Kiessling R, Mellstedt H, Österborg A, Lundqvist A. Dendritic cell regulation of NK-cell responses involves lymphotoxin-α, IL-12, and TGF-β. European journal of immunology 2015 45;6 1783-93

Mao Y*, Sarhan D*, Steven A, Seliger B, Kiessling R,  Lundqvist A. Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clinical cancer research: an official journal of the American Association for Cancer Research 2014 20;15 4096-106

Sarhan D, Wennerberg E,  D'Arcy P,  Gurajada D,  Linder S,  Lundqvist A. A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells. Cancer immunology, immunotherapy: CII 2013 62;8 1359-68

Wennerberg E, Sarhan D, Carlsten M, Kaminskyy VO,  D'Arcy P,  Zhivotovsky B,  Childs R,  Lundqvist A. Doxorubicin sensitizes human tumor cells to NK cell- and T-cell-mediated killing by augmented TRAIL receptor signaling. International journal of cancer 2013 133;7 1643-52

Sarhan D, D'Arcy P, Wennerberg E,  Lidén M,  Hu J,  Winqvist O,  Rolny C,  Lundqvist A. Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ. European journal of immunology 2013

Okita R, Mougiakakos D, Ando T,  Mao YM,  Sarhan D,  Wennerberg E,  Seliger B,  Lundqvist A,  Mimura K,  Kiessling R. HER2/HER3 Signaling Regulates NK Cell-Mediated Cytotoxicity via MHC Class I Chain-Related Molecule A and B Expression in Human Breast Cancer Cell Lines. JOURNAL OF IMMUNOLOGY 2012 188;5 2136-45

Reviews

Razaghi A, Poorebrahim M, Sarhan D, Björnstedt M. Selenium stimulates the antitumour immunity: Insights to future research. Eur J Cancer. 2021. 12;155:256-267

Dahlberg CI, Sarhan D,  Chrobok M,  Duru AD,  Alici E. Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity. Frontiers in immunology 2015 6; 605-

Sarhan D, D'Arcy P, Lundqvist A. Regulation of TRAIL-receptor expression by the ubiquitin-proteasome system. International journal of molecular sciences 2014 15;10 18557-73

Kiessling R, Okita R,  Mougiakakos D,  Mao YM,  Sarhan D,  Wennerberg E,  Seliger B,  Lundqvist A,  Mimura K,  Kono K. Opposing consequences of signaling through EGF family members Escape from CTLs could be a bait for NK cells. ONCOIMMUNOLOGY 2012 1;7 1200-1201

Book chapters

Sarhan D,  Miller JS. Cell and Gene Therapies, Natural Killer Cells-What have we learned?, Springer Nature, 2019

Sarhan D,  Miller JS. Immune checkpoint blockade, Assessing Canonical and Adaptive Natural Killer Cell Function in Suppression Assays In Vitro. Methods in molecular biology (Clifton, N.J.) 2019 1913; 153-166