In vivo imaging of spatial-temporal specific T cell activation and trafficking for evaluation and development of improved cancer therapies
Final Report Abstract
We have generated new transgenic mice models allowing us to visualize the spatial-temporal antigen-specific T cell activation and trafficking in different experimental settings. Instead of lentivirally transducing T cells with luciferase reporters for bioluminescence imaging in vivo, we have generated transgenic mice, which provide T cells exhibiting an NFAT-responsive enhancer, a red-shifted Clickbeetle luciferase and a constitutive Renilla luciferase. These transgenic mice are advantageous as a yielding and immediate source of T cells for ATT. Manipulations due to transduction or delay due to immune reconstitution of chimeric mice can be thereby bypassed. Further breeding resulted in T cells being additionally transgenic for a TCR specifically targeting the minor antigen H-Y, either on CD4 or CD8 T cells. Using our pool of different transgenic mice, we are now able to study ATT targeting H-Y-expressing tumors addressing following aspects: polyclonal vs. H-Y TCR transgenic T cells, CD4 vs. CD8 vs. combination and TSA vs. TAA, targeting tumor with varying levels of tumor antigen expression. Moreover, we have established expansion protocols to obtain sufficient numbers of central memory and effector memory T cells for comparative ATT studies of these two subsets in respect to migration and activation kinetics in tumor-bearing mice. In this context, we have additionally generated an IL-15 secreting cell line to cover the usage of high IL-15 amounts for the expansion of T cells. First experiments regarding combination treatment already revealed a benefit of earlier and stronger anti-tumor activity when irradiation is added to ATT. More combination protocols (different treatment schedules/ different treatment agents) are being tested and will be further evaluated.
Publications
- Rabbit antithymocyte globulin (thymoglobulin) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients. Haematologica 98(1), 23-30 (2013)
Na IK, Wittenbecher F, Dziubianau M, Herholz A, Mensen A, Kunkel D, Blau O, Blau I, Thiel E, Uharek L, Scheibenbogen C, Rieger K, Thiel A
(See online at https://doi.org/10.3324/haematol.2012.067611) - Rabbit antithymocyte globulin induces rapid expansion of effector memory CD8 T cells without accelerating acute graft versus host disease. Leuk Res Rep. 2(2), 82-5 (2013)
Wittenbecher F, Rieger K, Dziubianau M, Herholz A, Mensen A, Blau IW, Uharek L, Dörken B, Thiel A, Na IK
- Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation. J Transl Med.11, 188 (2013)
Mensen A1, Ochs C, Stroux A, Wittenbecher F, Szyska M, Imberti L, Fillatreau S, Uharek L, Arnold R, Dörken B, Thiel A, Scheibenbogen C, Na IK
- Bone marrow T-cell infiltration during acute GVHD is associated with delayed B-cell recovery and function after HSCT. Blood 124(6), 963-72 (2014)
Mensen A, Jöhrens K, Anagnostopoulos I, Demski S, Oey M, Stroux A, Hemmati P, Westermann J, Blau O, Wittenbecher F, Movassaghi K, Szyska M, Thomas S, Dörken B, Scheibenbogen C, Arnold R, Na IK
(See online at https://doi.org/10.1182/blood-2013-11-539031) - Comparison of different rabbit ATG preparation effects on early lymphocyte subset recovery after allogeneic HSCT and its association with EBV-mediated PTLD. J Cancer Res Clin Oncol 140(11),1971-80 (2014)
Mensen A, Na IK, Häfer R, Meerbach A, Schlecht M, Pietschmann ML, Gruhn B
(See online at https://doi.org/10.1007/s00432-014-1742-z)
