Project C7

Viroimmunotherapy in HCC: Recruitment and Expansion of Dendritic Cells by Tumor-Specific Replicating Viruses

Principal Investigators: Dr. Florian Kühnel


Short Summary

Virotherapy elicits antitumoral immune response by cross-presentation of tumor antigens. We showed that virotherapy can overcome tumor-specific immune-tolerance mechanisms and demonstrated improvement of virotherapy-induced antitumor immune response by recruitment and expansion of dendritic cells (DC) at the site of oncolytic viral infection. Aim of our project is the identification of cytokine/chemokine-combinations for optimized recruitment and expansion of DC. In addition, we will investigate the molecular mechanisms of virotherapy-induced cell death that support antitumoral immune response due to improved uptake and cross-presentation of tumor antigens by DC.

List of relevant publications

  1. Schache P, Gürlevik E, Strüver N, Malek NP, Zender L, Manns MP, Wirth T, Kühnel F*, Kubicka S* (2009) VSV virotherapy improves chemotherapy by triggering of apoptosis de to proteasomal degradation of MCL-1. Gene Therap,(in press).
  2. Ramakrishna E, Woller N, Mundt B, Knocke S, Gürlevik E, Saborowski M, Malek N, Wirth T, Kühnel F, Kubicka S (2009) Antitumoral immune response by recruitment and expansion of dendritic cells in tumors infected with telomerase-dependent oncolytic viruses. Cancer Research [Epub ahead of print]
  3. Zender L, Xue W, Zuber J, Semighini CP, Krasnitz A, Ma B, Zender P, Kubicka S, Luk JM, Schirmacher P, Richard McCombie W, Wigler M, Hicks J, Hannon GJ, Powers S, Lowe SW (2008) An Oncogenomics-Based In Vivo RNAi Screen Identifies Tumor Suppressors in Liver Cancer. Cell 135:852-64.
  4. Nickeleit I, Zender S, Sasse F, Geffers R, Brandes G, Sörensen I, Steinmetz H, Kubicka S, Carlomagno T, Menche D, Gütgemann I, Buer J, Gossler A, Manns M, Kalesse M, Frank R, Malek NP (2008) Argyrin A reveals a critical role for the tumor suppressor protein p27kip1 in mediating antitumor activities in response to proteasome inhibition. Cancer Cell 14:23-35.
  5. Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K, Schlegelberger B, Schirmacher P, Kunkel TA, Greenberg RA, Edelmann W, Rudolph KL (2007) Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice. Cell 130:863-77.
  6. Xue W, Krasnitz A, Lucito R, Sordella R, Vanaelst L, Cordon-Cardo C, Singer S, Kuehnel F, Wigler M, Powers S, Zender L, Lowe SW (2008) DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma. Genes Dev 22:1439-44.
  7. Lechel A, Holstege H, Begus Y, Schienke A, Kamino K, Lehmann U, Kubicka S, Schirmacher P, Jonkers J, Rudolph KL (2007) Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology 132:1465-75.
  8. Timmerbeul I, Garrett-Engele GM, Kossatz U, Chen X, Firpo E, Grünwald V, Kamino K, Wilkens L, Lehmann U, Buer J, Geffers R, Kubicka S, Manns MP, Porter PL, Roberts JM and Malek NP (2006) Testing the importance of p27 degradation by the SCF Skp2 pathway in murine models of lung and colon cancer. Proc Natl Acad Sci USA 103:14009-14.
  9. Ito H, Aoki H, Kuhnel F, Kondo Y, Kubicka S, Wirth T, Iwado E, Iwamaru A, Fujiwara K, Hess KR, Lang FF, Sawaya R, Kondo S (2006) Autophagic cell death of malignant glioma cells induced by a conditionally replicating adenovirus. J Natl Cancer Inst 98:625-36.
  10. Wirth T*, Kühnel F*, Fleischmann-Mundt B, Woller N, Djojosubroto M, Rudolph KL, Manns MP,  Zender L, Kubicka S (2005) Telomerase dependent virotherapy overcomes resistance of hepatocellular carcinomas against chemotherapy and TRAIL by elimination of MCL-1. Cancer Res 65:7393-402.
  11. Mundt B, Wirth T, Zender L, Waltemathe M, Trautwein C, Manns MP, Kühnel F, Kubicka S (2005) TNF-related apoptosis-inducing ligand (TRAIL) induces hepatic steatosis in viral hepatitis and after alcohol intake. Gut 54(11):1590-96.
  12. Zender L, Hütker S, Mundt B, Waltemathe M, Klein C, Trautwein C, Malek NP, Manns NP, Kühnel F, Kubicka S (2005) NFB mediated up-regulation of bcl-xl restrains trail-mediated apoptosis in viral hepatitis. Hepatology 19;41(2):280-88.
  13. Kühnel F, Schulte B, Wirth T, Woller N, Schäfers S, Zender L, Manns M, Kubicka S (2004) Protein transduction domains fused to virus receptor improve cellular virus uptake and enhance oncolysis by tumor specific replicating vectors. J. Virol 78:13743-54.
  14. Plentz RR, Caselitz M, Bleck JS, Gebel M, Flemming P, Kubicka S, Manns MP, Rudolph KL (2004) Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma. Hepatology 40:80-86.
  15. Kuhnel F, Fritsch C, Krause S, Mundt B, Wirth T, Paul Y, Malek NP, Zender L, Manns MP, Kubicka S (2004) Doxycyline regulation in a single retroviral vector by an autoregulatory loop facilitates controlled gene expression in liver cells. Nucleic Acids Res32:e30.
  16. Kuhnel F, Zender L, Wirth T, Schulte B, Trautwein C, Manns M, Kubicka S (2004) Tumor specific adenoviral gene therapy: transcriptional repression of gene expression by utilizing p53-signal transduction pathways. Cancer Gene Ther 11:28-40.
  17. Wirth T, Zender L, Schulte B, Mundt B, Plentz R, Rudolph KL, Manns M, Kubicka S, Kühnel F (2003). A telomerase dependent conditionally replicating adenovirus for selective treatment of cancer. Cancer Res 63:3181-88.
  18. Zender L, Hütker S, Liedke C, Tillmann HL, Zender S, Mundt B, Waltemathe M, Gösling T, Flemming P, Malek NP, Trautwein C, Manns M P, Kühnel F*, Kubicka S* (2003) Caspase 8 siRNA prevents acute liver failure in mice. Proc Natl Acad Sci USA 100:7797-802.
  19. Mundt B, Kühnel F, Zender L, Paul Y, Tillmann H, Trautwein C, Manns MP, Kubicka S (2003) Involvement of TRAIL and its receptors in viral hepatitis. FASEB J 17:94-96.
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