Abstract
Deregulation of apoptosis signalling is commonly found in cancer and results in resistance to cytotoxic therapies. Immunotherapy is a promising strategy to eliminate resistant cancer cells. The transfer of T-lymphocytes during allogeneic stem cell transplantation is clinically explored to induce a ‘graft-versus-tumor’ effect (GvT). Cytotoxic T-lymphocytes (CTL), which are major effectors of GvT, eliminate cancer cells by inducing apoptosis via multiple parallel pathways. Here, we study in vitro and in vivo the susceptibility of murine cancer cells engineered to express single antiapoptotic genes to CTL-mediated cytotoxicity. Interestingly, we find that single inhibitors of caspase activation, such as BCL-XL or dominant-negative mutants of FADD and caspase-9, protect cancer cells against antigen-specific CTL in vitro. Moreover, expression of BCL-XL impairs the growth suppression by adoptively transplanted CTL of established tumours in vivo. Hence, apoptosis defects that provide protection to cytotoxic cancer therapies can confer crossresistance to immunotherapy by tumour-reactive CTL.
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Abbreviations
- ASCT:
-
allogeneic stem cell transplantation
- DISC:
-
death-inducing signalling complex
- MEF:
-
murine embryo fibroblasts
- MOMP:
-
mitochondrial outer membrane permeabilization
- PI:
-
propidium iodide
- TAA:
-
tumour-associated antigen
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Acknowledgements
We thank Edite Antunes-Ferreira, Emmanuelle Vaniet and Markus Jülch for technical assistance. Drs. Jon Ashwell, Wulf Böcher, Toshio Kitamura, Arnold Levine, Scott Lowe, Linda Sherman and Inder Verma are thanked for providing reagents and mice. This work was supported by the Research Network ‘Immunotherapy of Cancer by Haematopoietic Stem Cell Transplantation’ of the Deutsche Krebshilfe (to MS and MT), by the MAIFOR-Programm (to MS, MT and JK) and by the ‘Tumor Vaccination Center’ of the Deutsche Krebshilfe. MT is a José Carreras Leukemia Foundation Professor.
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CH, NB and JK contributed equally to this work
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Huber, C., Bobek, N., Kuball, J. et al. Inhibitors of apoptosis confer resistance to tumour suppression by adoptively transplanted cytotoxic T-lymphocytes in vitro and in vivo. Cell Death Differ 12, 317–325 (2005). https://doi.org/10.1038/sj.cdd.4401563
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DOI: https://doi.org/10.1038/sj.cdd.4401563
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