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The immune system prevents recurrence of transplanted but not autochthonous antigenic tumors after oncogene inactivation therapy.
- Source :
-
International journal of cancer [Int J Cancer] 2017 Dec 15; Vol. 141 (12), pp. 2551-2561. Date of Electronic Publication: 2017 Aug 31. - Publication Year :
- 2017
-
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 <superscript>+</superscript> T cells targeting the cancer-driving oncogene eradicated recurrent autochthonous tumors, highlighting a suitable therapy option in a clinically relevant model.<br /> (© 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
- Subjects :
- Adoptive Transfer
Animals
Antigens, Polyomavirus Transforming genetics
Antigens, Polyomavirus Transforming metabolism
CD8-Positive T-Lymphocytes immunology
Cell Line, Tumor
Doxycycline therapeutic use
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasm Transplantation
Neoplasms, Experimental immunology
Recombinant Fusion Proteins genetics
CD8-Positive T-Lymphocytes transplantation
Doxycycline administration & dosage
Gene Silencing
Immune System metabolism
Neoplasms, Experimental therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 141
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 28833076
- Full Text :
- https://doi.org/10.1002/ijc.31009