Project A3

The role of natural killer cells for the transition from hepatitis to hepatocellular carcinoma

Principal Investigator: Prof. Dr. Christine S. Falk


Short summary
The presence of innate immune cells such as natural killer (NK) cells in the liver has been known for decades. However, the role of human NK cells as regulators of hepatocellular tumor growth has not yet been addressed in detail. Recently, tissue-resident NK cells with an unusual cytokine secretion pattern, i.e. NK-22 cells have been identified. The goal of this proposal is the identification of specialized NK cells in the liver and the definition of their role in HCC, either directly by tumor recognition or indirectly by destruction of the cytokine/chemokine micromilieu.


List of relevant publications

  1. Sers C, Kuner R, Falk CS, Lund P, Sueltmann H, Braun M, Buness A, Ruschhaupt M, Conrad J, Mang-Fatehi S, Stelniec I, Krapfenbauer U, Poustka A, Schäfer R (2009) Downregulation of HLA class I and NKG2D ligands through a concerted action of MAPK and DNA methyltransferases in colorectal cancer cells. Int J Canc in press.
  2. Kausche S, Wehler T, Schnurer E, Lennerz V, Brenner W, Melchior S, Grone M, Nonn M, Strand S, Meyer R, Ranieri E, Huber C, Falk CS, Herr W (2006) Superior antitumor in vitro responses of allogeneic matched sibling compared with autologous patient CD8+ T cells. Cancer Res 66:11447-54.
  3. Anfossi N, Andre P, Guia S, Falk CS, Roetynck S, Stewart CA, Breso V, Frassati C, Reviron D, Middleton D, Romagne F, Ugolini S, Vivier E (2006) Human NK cell education by inhibitory receptors for MHC class I. Immunity 25:331-42.
  4. Schleypen JS, Baur N, Kammerer R, Nelson PJ, Rohrmann K, Grone EF, Hohenfellner M, Haferkamp A, Pohla H, Schendel DJ, Falk CS, Noessner E (2006) Cytotoxic markers and frequency predict functional capacity of natural killer cells infiltrating renal cell carcinoma. Clin Cancer Res 12:718-25.
  5. von Geldern M, Simm B, Braun M, Weiss EH, Schendel DJ, Falk CS (2006) TCR-independent cytokine stimulation induces non-MHC-restricted T cell activity and is negatively regulated by HLA class I. Eur J Immunol 36:2347-58.
  6. Baratin M, Roetynck S, Lepolard C, Falk CS, Sawadogo S, Uematsu S, Akira S, Ryffel B, Tiraby JG, Alexopoulou L, Kirschning CJ, Gysin J, Vivier E, Ugolini S (2005) Natural killer cell and macrophage cooperation in MyD88-dependent innate responses to Plasmodium falciparum. Proc Natl Acad Sci U S A 102:14747-52.
  7. Aktas E, Akdis M, Bilgic S, Disch R, Falk CS, Blaser K, Akdis C, Deniz G (2005) Different natural killer (NK) receptor expression and immunoglobulin E (IgE) regulation by NK1 and NK2 cells. Clin Exp Immunol 140:301-09.
  8. Kurschus FC, Bruno R, Fellows E, Falk CS, Jenne DE (2005) Membrane receptors are not required to deliver granzyme B during killer cell attack. Blood 105:2049-58.
  9. Schleypen JS, Von Geldern M, Weiss EH, Kotzias N, Rohrmann K, Schendel DJ, Falk CS, Pohla H (2003) Renal cell carcinoma-infiltrating natural killer cells express differential repertoires of activating and inhibitory receptors and are inhibited by specific HLA class I allotypes. IntJCancer 106:905-12.
  10. Herzer K, Falk CS, Encke J, Eichhorst ST, Ulsenheimer A, Seliger B, Krammer PH (2003) Upregulation of major histocompatibility complex class I on liver cells by hepatitis C virus core protein via p53 and TAP1 impairs natural killer cell cytotoxicity. J Virol 77:8299-09
  11. Falk CS, Mach M, Schendel DJ, Weiss EH, Hilgert I, Hahn G (2002) NK cell activity during human cytomegalovirus infection is dominated by US2-11-mediated HLA class I down-regulation. J Immunol 169:3257-66.
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