IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner
- 14 May 2013
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 110 (20), 8158-8163
- https://doi.org/10.1073/pnas.1301022110
Abstract
A major challenge of cancer immunotherapy is the persistence and outgrowth of subpopulations that lose expression of the target antigen. IL-15 is a potent cytokine that can promote organ-specific autoimmunity when up-regulated on tissue cells. Here we report that T cells eradicated 2-wk-old solid tumors that expressed IL-15, eliminating antigen-negative cells. In contrast, control tumors that lacked IL-15 expression consistently relapsed. Interestingly, even tumors lacking expression of cognate antigen were rejected when expressing IL-15, indicating that rejection after adoptive T-cell transfer was independent of cognate antigen expression. Nevertheless, the T-cell receptor of the transferred T cells influenced the outcome, consistent with the notion that T-cell receptor activation and effector status determine whether IL-15 can confer lymphokine killer activity-like properties to T cells. The effect was limited to the microenvironment of tumors expressing IL-15; there were no noticeable effects on contralateral tumors lacking IL-15. Taken together, these results indicate that expression of IL-15 in the tumor microenvironment may prevent the escape of antigen loss variants and subsequent tumor recurrence by enabling T cells to eliminate cancer cells lacking cognate antigen expression in a locally restricted manner.Keywords
This publication has 39 references indexed in Scilit:
- Tissue-mediated control of immunopathology in coeliac diseaseNature Reviews Immunology, 2009
- Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15The Journal of Experimental Medicine, 2009
- Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapyEuropean Journal of Immunology, 2008
- The Innate NK Cells, Allograft Rejection, and a Key Role for IL-15The Journal of Immunology, 2008
- IL-15Rα chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentationThe Journal of Experimental Medicine, 2008
- Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T CellsCancer Research, 2008
- IFN-γ– and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancersJCI Insight, 2008
- Preassociation of IL-15 with IL-15Rα-IgG1-Fc Enhances Its Activity on Proliferation of NK and CD8+/CD44high T Cells and Its Antitumor ActionPublished by The American Association of Immunologists ,2008
- Designer T cells by T cell receptor replacementEuropean Journal of Immunology, 2006
- IL-15/IL-15 receptor biology: A guided tour through an expanding universeCytokine & Growth Factor Reviews, 2006