Bildgebung von NK Zell Reaktivität in der Tumor-Immuntherapie
Zusammenfassung der Projektergebnisse
The success story of therapeutic antibodies so far is often limited by i) antibody efficacy and ii) the lack of suitable target antigens for cancers where so far no immunotherapeutic intervention is available. Therefore, this project has focused on improving immunotherapeutic options for patients with malignant disease. In the first part of the project we developed a novel strategy which may facilitate prediction of treatment success and thus serve better clinical decision making. We engineered an antibody-like construct which targets a tumor antigen, carcinoembryonic antigen (CEA), and which can be released by cells, e.g. adoptively transferred CAR-T cells. The construct contained a SNAP/CLIP-tag which can readily conjugate with chemical derivatives of theranostic (therapeutic and diagnostic) moieties and direct those compounds to CEA- expressing tumors. Engineering CAR-T to secrete these antibody-like biologicals would allow for dual targeting and thus reach tumor cells which escape monotherapy. Since Natural Killer (NK) cells and induction of antibody-dependent cellular cytotoxicity (ADCC) plays an important role in the efficacy of antitumor antibodies, another goal of this project was to test Fc-optimization as means to enhance antibody function. We employed an antibody targeting ligands of the activating receptor natural killer group 2D (NKG2D/NKG2DL) which are expressed upon cellular stress / malignant transformation. This, together with the fact that they are generally absent on healthy cells, makes them bona fide antigens for targeted therapy. Tumor cells can escape immune recognition by proteolytic cleavage of NKG2DL from the cell surface. Our antibody 7C6 is able to bind to the immune activating NKG2D ligands MICA/B and stabilize their expression by inhibition of shedding. We Fc-optimized this antibody (7C6-GAALIE) to enhance its affinity to CD16, the main activating receptor on NK cells, which resulted in superior induction of NK antitumor reactivity. This was particularly true when combining 7C6-GAALIE with the FDA approved histone-deacetylase inhibitor Romidepsin which furthers MICA/B upregulation. Together, these findings indicate that 7C6-GAALIE promotes NK cell-mediated immunity against AML cells by dual molecular mechanism: 1) preservation of MICA/B for NKG2D recognition, and 2) strong triggering of Fc activating receptors. Therefore, 7C6-GAALIE plus romidepsin constitutes an attractive regimen for immunotherapy research.
Projektbezogene Publikationen (Auswahl)
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NK Cell Interaction With Platelets and Myeloid Cells in the Tumor Milieu. Frontiers in Immunology, 11.
Maurer, Stefanie & Ferrari, de Andrade Lucas
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Platelet-expressed immune checkpoint regulator GITRL in breast cancer. Cancer Immunology, Immunotherapy, 70(9), 2483-2496.
Zhou, Yanjun; Heitmann, Jonas S.; Clar, Kim L.; Kropp, Korbinian N.; Hinterleitner, Martina; Engler, Tobias; Koch, André; Hartkopf, Andreas D.; Zender, Lars; Salih, Helmut R.; Maurer, Stefanie & Hinterleitner, Clemens
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Platelet-Expressed TNFRSF13B (TACI) Predicts Breast Cancer Progression. Frontiers in Oncology, 11.
Hinterleitner, Clemens; Zhou, Yanjun; Tandler, Claudia; Heitmann, Jonas S.; Kropp, Korbinian N.; Hinterleitner, Martina; Koch, André; Hartkopf, Andreas D.; Zender, Lars; Salih, Helmut R. & Maurer, Stefanie
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Regulation of Platelet-Derived ADAM17: A Biomarker Approach for Breast Cancer?. Diagnostics, 11(7), 1188.
Zhou, Yanjun; Heitmann, Jonas S.; Kropp, Korbinian N.; Hinterleitner, Martina; Koch, André; Hartkopf, Andreas D.; Salih, Helmut R.; Hinterleitner, Clemens & Maurer, Stefanie
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Controversial Role of the Immune Checkpoint OX40L Expression on Platelets in Breast Cancer Progression. Frontiers in Oncology, 12.
Rittig, Susanne M.; Lutz, Martina S.; Clar, Kim L.; Zhou, Yanjun; Kropp, Korbinian N.; Koch, André; Hartkopf, Andreas D.; Hinterleitner, Martina; Zender, Lars; Salih, Helmut R.; Maurer, Stefanie & Hinterleitner, Clemens
