Field of Study

Our lab focuses of the natural killer cell, part of the innate immune system. We research these cells in both humans and mice, from molecular biology all the way to clinical application, including drug development.

Research Interests

Cancer

Natural killer cells are an important part of our immunosurveillance system, so their ability to recognize and kill cancerous cells is of particular interest. Work in our lab has looked into the effect of immunoediting by NK cells, and we recently showed that an NK activating receptor, NKp46, influences FN1 expression by tumors, ultimately affecting metastatic ability (Glasner et al. Immunity 2018). We have also discovered immune-evasion properties of oncogenes, helping to understand the clinical importance of these mutations (Elias et al. Blood 2014). Our understanding of inhibitory receptors on NK cells has even allowed us to generate novel checkpoint inhibitors, including one which is currently in pre-clinical development (NectinTX).

Pregnancy

Peter Medewar famously asked how the maternal immune system tolerates the semi-allogeneic fetus. While this question remains unanswered, understanding of NK cells, which make up a majority of the lymphocytes in the human placenta in the first trimester of pregnancy, may help solve this mystery. We showed that NK cells in the placenta are not merely involved in immunity, but also influence the developmental processes of tissues supporting the fetus (Hanna et al. Nature Medicine 2006).

More recently, we also showed that NK cells remember pregnancy (Gamliel et al. Immunity 2018). Following a woman’s first pregnancy, a subset of trained NK cells waits in the uterus for the next pregnancy. If this pregnancy arrives, the NK cells are ready to secrete a variety of factors and help the placenta develop. This may help explain some of the increased risks in first pregnancy which have been linked to poor placental development.

Viruses

NK cells are also the cornerstone of the body’s response to infection by a variety of viruses. People with mutations impairing NK function are at increased susceptibility to viral infection, especially with herpesviruses. We study a number of viruses in our lab, including influenza, CMV, HSV-1, HHV-6/7, HMPV, Zika, and reovirus.

Viruses are quite complex, many existing latently for a host’s whole life, so naturally they have developed many mechanisms for evading the human immune system. This has been a field of particular interest in our group (Glasner et al. J Virology 2018, Charpak-Amikam et al. Scientific Reports 2018, Enk et al. Cell Reports 2017, Diab et al. Oncotarget 2016, Schmiedel et al. J Virology 2016, Yamin et al. Cell Reports 2016, Bauman et al. Oncotarget 2016, Schmiedel et al. Elife 2016, Seidel et al. Cell Reports 2015). We were, in fact, the first to show viral targeting of human transcripts using miRNAs (Stern-Ginossar et al. Science 2007).

We also study direct interaction between NK receptors and viruses (Mandelboim et al. Nature 2001, Bar-On et al, J Virology 2017, Duev-Cohen et al. Oncotarget 2016, Diab et al. Oncotarget 2016). As we have seen in cancer immunotherapy, understanding the immune response at this level can have great therapeutic potential.

Immune Regulation

Our interests also include a closer look at the molecular biology regulating immune function, particularly at the RNA level. We have found several RNA binding proteins which regulate various immune molecules (Berhani et al. J Immunology 2017, Reches et al. J immunology 2017, Nachmani et al. Nature Communications 2014). mRNA stability and miRNAs are also an important part of immune regulation related to NK cells (Toledano et al. J Immunlogy 2018, Tsukerman et al. Oncotarget 2014, Tsukerman et al. Cancer Research 2012, Nachmani et al. Nature Immunology 2010).

Bacteria and Fungi

Recent work has shown that NK cells are important in the immune response to bacteria and fungi. We found that certain bacteria can directly bind NK receptors, altering NK function (Gur et al. Immunity 2015). We also found that common fungal pathogens such as Candida glabrata are directly recognized by NK cells (Vitenshtein et al. Cell Host and Microbe 2016). Our work on Fusobacterium nucleatum may help explain the worse prognosis observed in patients with colorectal cancer colonized by F. nucleatum, and guide future treatment of these patients.

Other works in our lab showed that NK cells are involved in urinary tract infections, one of the most common bacterial infections in humans (Isaacson et al. Cell Reports 2017, Gur et al. Cell Host and Microbe 2013). This understanding has helped us develop new immune-stimulatory treatments for cancer.

Lab Alumni

1. Dr. Sharon Nordheimer
2. Dr. Moriya Gamliel
3. Dr. Dominik Schmiedel
4. Prof. Jacob Hanna
5. Dr. Roi Gazit
6. Dr. Gil Katz
7. Dr. Noam Stern-Ginossar
8. Dr. Pinchas Tsukerman
9. Dr. Noa Kaynan
10. Dr. Moran Elboim
11. Prof. Gal Markel
12. Dr. Gili Halfteck
13. Dr. Ariella Glasner
14. Dr. Rachel Yamin
15. Dr. Alon Vitenshtein
16. Dr. Dikla Lankry
17. Dr. Yoav Bauman
18. Yael Ophir
19. Dr. Irit Manaster
20. Dr. Raizy Gruda
21. Dr. Gili Betser-Cohen
22. Dr. Saar Mizrahi
23. Dr. Yonatan Enk
24. Dr. Dafna Nachmani
25. Dr. Hormas Ghadially
26. Dr. Yotam Bar-On
27. Dr. Mohammad Diab
28. Dr. Noa Stanietsky
29. Prof. Stella Chaushu
30. Dr. Chamutal Gur
31. Dr. Tal Goldberger
32. Dr. Shlomo Elias

Cancer Immunotherapy

TIGIT serves as an inhibitory receptor on human NK cells

Stanietsky et al. PNAS. 2009

Company Founded: TIGIT and PVR blocking-antibodies as novel immune checkpoint inhibitors with funding from Integra and Orbimed

Bacteria

Fusobacterium nucleatum protects colorectal cancer from immune attack

Gur et al. Immunity. 2012

NK cells respond to urinary tract infection, and UPEC has learned to adhere to and kill NKs Gur et al. Cell Host and Microbe. 2013.

Company Founded: UPEC for treatment of bladder cancer with funding from Integra

Viruses

Viral micro-RNAs can target human genes

Stern-Ginossar et al. Science. 2007

HCMV successfully targets a human escape variant in order to avoid NK attack

Seidel E et al. Cell Reports. 2015

Molecular Biology

RNA binding proteins can control expression levels of NK ligands

Nachmani et al. Nat Communications. 2014

IMP3 aids viral escape by downregulating NK activating ligands

Shmeidel et al. Elife. 2016

Fungi

NKs recognize and kill fungi, including Candida glabrata

Vitenshtein et al. Cell Host Microbe. 2016

Publications

1. Glasner A, Levi A, Enk J, Isaacson B, Viukov S, Orlanski S, Scope A, Neuman T, Enk CD, Hanna JH, Sexl V, Jonjic S, Seliger B, Zitvogel L, Mandelboim O. NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis. Immunity. 2018 Jan 16;48(1):107-119.e4.
2. Levi-Schaffer F, Mandelboim O. Inhibitory and Coactivating Receptors Recognising the Same Ligand: Immune Homeostasis Exploited by Pathogens and Tumours. Trends Immunol. 2017 Oct 20. 
3. Glasner A, Isaacson B, Viukov S, Neuman T, Friedman N, Mandelboim M, Sexl V, Hanna JH, Mandelboim O. Increased NK cell immunity in a transgenic mouse model of NKp46 overexpression. Sci Rep. 2017 Oct 12;7(1):13090.
4. Glasner A, Oiknine-Djian E, Weisblum Y, Diab M, Panet A, Wolf DG, Mandelboim O. Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules. J Virol. 2017 Oct 27;91(22).
5. Charpak-Amikam Y, Kubsch T, Seidel E, Oiknine-Djian E, Cavaletto N, Yamin R, Schmiedel D, Wolf D, Gribaudo G, Messerle M, Cicin-Sain L, Mandelboim O. Human cytomegalovirus escapes immune recognition by NK cells through the downregulation of B7-H6 by the viral genes US18 and US20. Sci Rep. 2017 Aug 17;7(1):8661.
6. Bar-On Y, Charpak-Amikam Y, Glasner A, Isaacson B, Duev-Cohen A, Tsukerman P, Varvak A, Mandelboim M, Mandelboim O. NKp46 Recognizes the Sigma1 Protein of Reovirus: Implications for Reovirus-Based Cancer Therapy. J Virol. 2017 Sep 12;91(19).
7. Abed J, Maalouf N, Parhi L, Chaushu S, Mandelboim O, Bachrach G. Tumor Targeting by Fusobacterium nucleatum: A Pilot Study and Future Perspectives. Front Cell Infect Microbiol. 2017 Jun 30;7:295.
8. Isaacson B, Hadad T, Glasner A, Gur C, Granot Z, Bachrach G, Mandelboim O. Stromal Cell-Derived Factor 1 Mediates Immune Cell Attraction upon Urinary Tract Infection. Cell Rep. 2017 Jul 5;20(1):40-47.
9. Miletic A, Lenartic M, Popovic B, Brizic I, Trsan T, Miklic K, Mandelboim O, Krmpotic A, Jonjic S. NCR1-deficiency diminishes the generation of protective murine cytomegalovirus antibodies by limiting follicular helper T-cell maturation. Eur J Immunol. 2017 Sep;47(9):1443-1456.
10. Schmiedel D, Mandelboim O. Disarming Cellular Alarm Systems-Manipulation of Stress Induced NKG2D Ligands by Human Herpesviruses. Front Immunol. 2017 Apr 11;8:390.
11. Eichmüller SB, Osen W, Mandelboim O, Seliger B. Immune Modulatory microRNAs Involved in Tumor Attack and Tumor Immune Escape. J Natl Cancer Inst. 2017 Apr 5.
12. Berhani O, Nachmani D, Yamin R, Schmiedel D, Bar-On Y, Mandelboim O. Vigilin Regulates the Expression of the Stress-Induced Ligand MICB by Interacting with It’s 5′ Untranslated Region. J Immunol. 2017 May 1;198(9):3662-3670.
13. Diab M, Glasner A, Isaacson B, Bar-On Y, Drori Y, Yamin R, Duev-Cohen A, Danziger O, Zamostiano R, Mandelboim M, Jonjic S, Bacharach E, Mandelboim O. NK-cell receptors NKp46 and NCR1 control human metapneumovirus infection. Eur J Immunol. 2017 Apr;47(4):692-703.
14. Glasner A, Isaacson B, Mandelboim O. Expression and function of NKp46 W32R: the human homologous protein of mouse NKp46 W32R (Noé). Sci Rep. 2017 Jan 30;7:40944.
15. Stein N, Tsukerman P, Mandelboim O. The paired receptors TIGIT and DNAM-1 as targets for therapeutic antibodies. Hum Antibodies. 2017;25(3-4):111-119.
16. Enk J, Levi A, Weisblum Y, Yamin R, Charpak-Amikam Y, Wolf DG, Mandelboim O.HSV1 MicroRNA Modulation of GPI Anchoring and Downstream Immune Evasion. Cell Rep. 2016 Oct 18;17(4):949-956.
17. Vitenshtein A, Charpak-Amikam Y, Yamin R, Bauman Y, Isaacson B, Stein N,Berhani O, Dassa L, Gamliel M, Gur C, Glasner A, Gomez C, Ben-Ami R, Osherov N, Cormack BP, Mandelboim O. NK Cell Recognition of Candida glabrata through Binding of NKp46 and NCR1 to Fungal Ligands Epa1, Epa6, and Epa7. Cell Host Microbe. 2016 Oct 12;20(4):527-534.
18. Diab M, Vitenshtein A, Drori Y, Yamin R, Danziger O, Zamostiano R, Mandelboim M, Bacharach E, Mandelboim O. Suppression of human metapneumovirus (HMPV) infection by the innate sensing gene CEACAM1. Oncotarget. 2016 Oct 11;7(41):66468-66479.
19. Schmiedel D, Tai J, Levi-Schaffer F, Dovrat S, Mandelboim O. Human  Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells. J Virol. 2016 Oct 14;90(21):9608-9617.  
20. Lenac Rovis T, Kucan Brlic P, Kaynan N, Juranic Lisnic V, Brizic I, Jordan S,Tomic A, Kvestak D, Babic M, Tsukerman P, Colonna M, Koszinowski U, Messerle M, Mandelboim O, Krmpotic A, Jonjic S. Inflammatory monocytes and NK cells play a crucial role in DNAM-1-dependent control of cytomegalovirus infection. J Exp Med. 2016 Aug 22;213(9):1835-50. doi: 10.1084/jem.20151899.
21. Vitenshtein A, Weisblum Y, Hauka S, Halenius A, Oiknine-Djian E, Tsukerman P, Bauman Y, Bar-On Y, Stern-Ginossar N, Enk J, Ortenberg R, Tai J, Markel G, Blumberg RS, Hengel H, Jonjic S, Wolf DG, Adler H, Kammerer R, Mandelboim O. CEACAM1-Mediated Inhibition of Virus Production. Cell Rep. 2016 Jun14;15(11):2331-9.
22. Reches A, Nachmani D, Berhani O, Duev-Cohen A, Shreibman D, Ophir Y, Seliger B, Mandelboim O. HNRNPR Regulates the Expression of Classical and Nonclassical MHC Class I Proteins. J Immunol. 2016 Jun 15;196(12):4967-76.
23. Yamin R, Lecker LS, Weisblum Y, Vitenshtein A, Le-Trilling VT, Wolf DG, Mandelboim O. HCMV vCXCL1 Binds Several Chemokine Receptors and Preferentially Attracts Neutrophils over NK Cells by Interacting with CXCR2. Cell Rep. 2016 May 17;15(7):1542-53.
24. Baía D, Pou J, Jones D, Mandelboim O, Trowsdale J, Muntasell A, López-Botet M. Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers. Eur J Immunol. 2016 Jul;46(7):1681-90.
25. Jasinski-Bergner S, Reches A, Stoehr C, Massa C, Gonschorek E, Huettelmaier S, Braun J, Wach S, Wullich B, Spath V, Wang E, Marincola FM, Mandelboim O, Hartmann A, Seliger B. Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma. Oncotarget. 2016 May 3;7(18):26866-78.
26. Ophir Y, Duev-Cohen A, Yamin R, Tsukerman P, Bauman Y, Gamliel M, Mandelboim O. PILRα binds an unknown receptor expressed primarily on CD56bright and decidual-NK cells and activates NK cell functions. Oncotarget. 2016 Jul 5;7(27):40953-40964.
27. Bauman Y, Drayman N, Ben-Nun-Shaul O, Vitenstein A, Yamin R, Ophir Y, Oppenheim A, Mandelboim O. Downregulation of the stress-induced ligand ULBP1 following SV40 infection confers viral evasion from NK cell cytotoxicity. Oncotarget. 2016 Mar 29;7(13):15369-81.
28. Schmiedel D, Tai J, Yamin R, Berhani O, Bauman Y, Mandelboim O. The RNA binding protein IMP3 facilitates tumor immune escape by downregulating the stress-induced ligands ULPB2 and MICB. Elife. 2016 Mar 16;5.
29. Houston A, Williams JM, Rovis TL, Shanley DK, O’Riordan RT, Kiely PA, Ball M, Barry OP, Kelly J, Fanning A, MacSharry J, Mandelboim O, Singer BB, Jonjic S, Moore T. Pregnancy-specific glycoprotein expression in normal gastrointestinal tract and in tumors detected with novel monoclonal antibodies. MAbs. 2016;8(3):491-500.
30. Duev-Cohen A, Bar-On Y, Glasner A, Berhani O, Ophir Y, Levi-Schaffer F, Mandelboim M, Mandelboim O. The human 2B4 and NTB-A receptors bind the influenza viral hemagglutinin and co-stimulate NK cell cytotoxicity. Oncotarget. 2016 Mar 15;7(11):13093-105.
31. Tsukerman P, Eisenstein EM, Chavkin M, Schmiedel D, Wong E, Werner M, Yaacov B, Averbuch D, Molho-Pessach V, Stepensky P, Kaynan N, Bar-On Y, Seidel E, Yamin R, Sagi I, Elpeleg O, Mandelboim O. Cytokine secretion and NK cell activity in human ADAM17 deficiency. Oncotarget. 2015 Dec 29;6(42):44151-60. doi:
32. Okada K, Sato S, Sato A, Mandelboim O, Yamasoba T, Kiyono H. Identification and Analysis of Natural Killer Cells in Murine Nasal Passages. PLoS One. 2015 Nov 17;10(11):e0142920.
33. Gur C, Mandelboim O, Bachrach G. “Messieurs, c’est les microbes qui auront le dernier mot”: Gentlemen, it is the microbes who have the last word (Louis Pasteur)-Fusobacterium nucleatum protect tumors from killing by immune cells. Oncoimmunology. 2015 May 27;4(9):e1038690.
34. Glasner A, Simic H, Miklić K, Roth Z, Berhani O, Khalaila I, Jonjic S, Mandelboim O. Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé. J Immunol. 2015 Oct 15;195(8):3959-69.
35. Weisblum Y, Panet A, Zakay-Rones Z, Vitenshtein A, Haimov-Kochman R, Goldman-Wohl D, Oiknine-Djian E, Yamin R, Meir K, Amsalem H, Imbar T, Mandelboim O, Yagel S, Wolf DG. Human cytomegalovirus induces a distinct innate immune response in the maternal-fetal interface. Virology. 2015 Nov;485:289-96.
36. Levi I, Amsalem H, Nissan A, Darash-Yahana M, Peretz T, Mandelboim O, Rachmilewitz J. Characterization of tumor infiltrating natural killer cell subset. Oncotarget. 2015 May 30;6(15):13835-43.
37. Wensveen FM, Jelenčić V, Valentić S, Šestan M, Wensveen TT, Theurich S, Glasner A, Mendrila D, Štimac D, Wunderlich FT, Brüning JC, Mandelboim O, Polić B. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol. 2015 Apr;16(4):376-85.
38. Yossef R, Gur C, Shemesh A, Guttman O, Hadad U, Nedvetzki S, Miletić A, Nalbandyan K, Cerwenka A, Jonjic S, Mandelboim O, Porgador A. Targeting natural killer cell reactivity by employing antibody to NKp46: implications for type 1 diabetes. PLoS One. 2015 Feb 26;10(2):e0118936.
39. Seidel E, Le VT, Bar-On Y, Tsukerman P, Enk J, Yamin R, Stein N, Schmiedel D, Oiknine Djian E, Weisblum Y, Tirosh B, Stastny P, Wolf DG, Hengel H, Mandelboim O. Dynamic Co-evolution of Host and Pathogen: HCMV Downregulates the Prevalent Allele MICA∗008 to Escape Elimination by NK Cells. Cell Rep. 2015 Feb 12.
40. Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M, Enk J, Bar-On Y, Stanietsky-Kaynan N, Coppenhagen-Glazer S, Shussman N, Almogy G, Cuapio A, Hofer E, Mevorach D, Tabib A, Ortenberg R, Markel G, Miklić K, Jonjic S, Brennan CA, Garrett WS, Bachrach G, Mandelboim O. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015 Feb 17;42(2):344-55.
41. Glasner A, Roth Z, Varvak A, Miletic A, Isaacson B, Bar-On Y, Jonjic S,Khalaila I, Mandelboim O. Identification of putative novel O-glycosylations in the NK killer receptor Ncr1 essential for its activity. Cell Discov. 2015 Dec 22;1:15036. doi: 10.1038/celldisc.2015.36.
42. Brusilovsky M, Radinsky O, Cohen L, Yossef R, Shemesh A, Braiman A,Mandelboim O, Campbell KS, Porgador A. Regulation of natural cytotoxicityreceptors by heparan sulfate proteoglycans in -cis: A lesson from NKp44. Eur J Immunol. 2015 Apr;45(4):1180-91.
43. Tsukerman P, Yamin R, Seidel E, Khawaled S, Schmiedel D, Bar-Mag T, Mandelboim O. MiR-520d-5p directly targets TWIST1 and downregulates the metastamiR miR-10b. Oncotarget. 2014 Dec 15;5(23):12141-50.
44. Gotthardt D, Prchal-Murphy M, Seillet C, Glasner A, Mandelboim O, Carotta S,  Sexl V, Putz EM. NK cell development in bone marrow and liver: site matters. Genes Immun. 2014 Dec;15(8):584-7.
45. Goldberger T, Mandelboim O. Editorial introduction for Seminars in Immunopathology special issue on “immune modulation, properties, and models of CMV”. Semin Immunopathol. 2014 Nov;36(6):611-3.
46. Goldberger T, Mandelboim O. The use of microRNA by human viruses: lessons from NK cells and HCMV infection. Semin Immunopathol. 2014 Nov;36(6):659-74. doi: 10.1007/s00281-014-0447-3. Epub 2014 Sep 19. Review.
47. Jasinski-Bergner S, Mandelboim O, Seliger B. The role of microRNAs in the control of innate immune response in cancer. J Natl Cancer Inst. 2014 Sep 12;106(10).
48. Nachmani D, Gutschner T, Reches A, Diederichs S, Mandelboim O. RNA-binding proteins regulate the expression of the immune activating ligand MICB. Nat Commun. 2014 Jun 13;5:4186.
49. Ghadially H, Ohana M, Elboim M, Gazit R, Gur C, Nagler A, Mandelboim O. NK cell receptor NKp46 regulates graft-versus-host disease. Cell Rep. 2014 Jun 26;7(6):1809-14.
50. Nachmani D, Zimmermann A, Oiknine Djian E, Weisblum Y, Livneh Y, Khanh Le VT, Galun E, Horejsi V, Isakov O, Shomron N, Wolf DG, Hengel H, Mandelboim O. microRNA editing facilitates immune elimination of HCMV infected cells. PLoS Pathog. 2014 Feb 27;10(2):e1003963.
51. Bar-On Y, Seidel E, Tsukerman P, Mandelboim M, Mandelboim O. Influenza virus uses its neuraminidase protein to evade the recognition of two activating NK cell receptors. J Infect Dis. 2014 Aug 1;210(3):410-8.
52. Enk J, Mandelboim O. The role of natural cytotoxicity receptors in various pathologies: emphasis on type I diabetes. Front Immunol. 2014 Jan 20;5:4.
53. Tsukerman P, Stern-Ginossar N, Yamin R, Ophir Y, Stanietsky AM, Mandelboim O. Expansion of CD16 positive and negative human NK cells in response to tumor stimulation. Eur J Immunol. 2014 May;44(5):1517-25.

Elias S, Yamin R, Golomb L, Tsukerman P, Stanietsky-Kaynan N, Ben-Yehuda D, Mandelboim O. Immune evasion by oncogenic proteins of acute myeloid leukemia. Blood. 2014 Mar 6;123(10):1535-43.