Contact

 

Priv-Doz. Dr. Frank Momburg
+49 (0) 6221-423726
f.momburg@dkfz-heidelberg.de

Activation and tissue targeting...

 

enhance T/NK cell cytotoxicity against tumors.

Antigen Presentation & T/NK Cell Activation

 
 
 

Recombinant MHC molecules for T cell in vitro diagnostics

We develop novel multiplex platforms for the in vitro diagnostics of tumor-antigen specific T cells (joint project with Dr. Zörnig/Prof. Jäger). We use soluble recombinant MHC-I and MHC-II Fc fusion proteins from various HLA-A,B,C and HLA-DR alloforms that are covalently conjugated with peptide ligands of choice (“pMHC”, Fig. 1) and bound to color-coded cytokine catcher beads. Our own recombinant pMHC-I and pMHC-II molecules are also used to quantitate tumor-specific T cell subpopulations by flow cytometry with high sensitivity. As novel tools for tumor targeting of T cells with selected specificities, we develop fusions proteins that combine tumor-specific single-chain antibodies with pMHC-I molecules (preloaded with peptides from viral recall antigens) in order to recruit viral epitope-specific, cytotoxic T cells towards tumors.

Adaptive natural killer cells for tumor therapy

Adaptive Natural Killer (aNK) cells represent a subset of NK cells which seems to be induced primarily by human cytomegalovirus infection. We recently deciphered parameters governing the expansion and activation of aNK cells (1, Fig. 2). Most adaptive NK cells are characterized by expression of the activating receptor NKG2C, deficiencies in multiple intracellular signalling molecules and transcription factors and a remarkably high capacity to mediate antibody-dependent cellular cytotoxicity. Strikingly, they display a substantially increased resilience to reactive oxygen species (ROS) compared to conventional NK cells. The presence of aNK cells is linked to a better prognosis in AML patients. Together, these emerging lines of evidence suggest a potent capacity for anti-tumor responses. Using recombinant peptide-loaded HLA-E-Fc fusion proteins constructed in our laboratory we can selectively activate and expand NKG2C+ aNK cells. We aim to utilize such aNK cells in adoptive NK cells transfer regimens for the treatment of myeloid leukemia and solid cancers.

Targeting of cytotoxic immune effector cells to tumor endothelium

The proper targeting of tumor-reactive cytotoxic effector cells (CD8+ T cells, NK cells) to tumor tissues appears to be an essential prerequisite for a successful immune cell-mediated tumor eradication. In an ongoing EU project we attempt to improve targeting of cytotoxic effector cells to tumor endothelial cells (TEC) by setting locally confined activating stimuli to TEC and then guiding T and NK cells towards TEC-specific receptors. Paradigmatically, we study the TEC binding and transmigration of T cells and NK cells using PSGL-1 fusions with anti-CD3 (or anti-CD56) single-chain antibodies that are intended to target cytotoxic effectors to E-selectin which is only expressed on activated tumor endothelium (Fig. 3).

Our group/department has:

  1. Demonstrated a key role for HLA-E-NKG2C as well as CD2-CD58 interactions for the activation and/or expansion of adaptive NK cells.
  2. Developed a novel bispecific antibody format for the treatment of HBV infection and HBV-associated hepatocellular carcinoma.

5 most significant publications

  1. Rölle, A, Halenius A, Ewen EM, Cerwenka A, Hengel H, and Momburg, F. Pivotal role of CD2-CD58 interactions for the activation and function of adaptive Natural Killer cells in human cytomegalovirus infection. Eur J Immunol. 46:2420-2425, 2016.
  2. Jarahian, M, Fiedler, M, Cohnen, A, Djandji, D, Hämmerling, GJ, Gati, C, Cerwenka, A, Turner, PC, Moyer, RW, Watzl, C, Hengel, H, and Momburg, F. Modulation of NKp30- and NKp46-mediated natural killer cell responses by poxviral hemagglutinin. PLoS Pathogens 7:e1002195, 2011.
  3. Koopmann JO, Albring J, Hüter E, Bulbuc N, Spee P, Neefjes J, Hämmerling GJ, and Momburg, F. Export of antigenic peptides from the endoplasmic reticulum intersects with retrograde protein translocation through the Sec61p channel. Immunity 13:117-27, 2000.
  4. Hengel, H, Koopmann, JO, Flohr, T, Muranyi, W, Goulmy, E, Hämmerling, GJ, Koszinowski, UH, and Momburg, F. A viral ER resident glycoprotein inactivates the MHC encoded peptide transporter. Immunity 6:623-632, 1997.
  5. Momburg F, Roelse J, Howard JC, Butcher GW, Hämmerling GJ, and Neefjes JJ. Selectivity of MHC-encoded peptide transporters from human, mouse, and rat. Nature 367:648-651, 1994.

Fundings

  • Helmholtz Validation Funds (together with Prof. Dr. U. Protzer, HMGU Munich)
  • EU Marie-Curie ITN (together with PD Dr. Schwartz-Albiez, DKFZ)