The immune system prevents recurrence of transplanted but not autochthonous antigenic tumors after oncogene inactivation therapy |
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| Authors: | Kathleen Anders Olivia Kershaw Lionel Larue Achim D. Gruber Thomas Blankenstein |
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| Affiliation: | 1. Max‐Delbrück‐Center for Molecular Medicine, Berlin, Germany;2. Institute of Veterinary Pathology, Berlin, Germany;3. Normal and Pathological Development of Melanocytes, 91405 Orsay, France;4. Centre National de la Recherche Scientifique (CNRS) UMR3347, 91405 Orsay, France;5. INSERM U1021, 91405 Orsay, France;6. Equipe Labellisee e Ligue Nationale contre le Cancer, 91405 Orsay, France;7. Institute of Immunology, Charité Campus Berlin Buch, Berlin, Germany;8. Berlin Institute of Health, Berlin, Germany |
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| Abstract: | ![]()
Targeted oncogene inactivation by small molecule inhibitors can be very effective but tumor recurrence is a frequent problem in the clinic. Therapy by inactivation of the cancer‐driving oncogene in transplanted tumors was shown to be augmented in the presence of T cells. However, these experiments did not take into account the long‐term, usually tolerogenic, interaction of de novo malignancies with the immune system. Here, we employed mice, in which SV40 large T (Tag) and firefly luciferase (Luc) as fusion protein (TagLuc) could be regulated with the Tet‐on system and upon activation resulted in tumors after a long latency. TagLuc inactivation induced profound tumor regression, demonstrating sustained oncogene addiction. While tumor relapse after TagLuc inactivation was prevented in immunocompetent mice bearing transplanted tumors, autochthonous tumors relapsed or recurred after therapy discontinuation indicating that the immune system that coevolved with the malignancy over an extended period of time lost the potency to mount an efficient anti‐tumor immune response. By contrast, adoptively transferred CD8+ T cells targeting the cancer‐driving oncogene eradicated recurrent autochthonous tumors, highlighting a suitable therapy option in a clinically relevant model. |
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| Keywords: | small molecule inhibitor oncogene addiction immunogenic cell death autochthonous tumor adoptive T cell therapy |
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