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Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 4/17/2012, Vol. 109 Issue 16, p6187-6192, 6p
- Publication Year :
- 2012
-
Abstract
- IL-15 has potential as an immunotherapeutic agent for cancer treatment because of its ability to effectively stimulate CD8 T cell, natural killer T cell, and natural killer cell immunity. However, its effectiveness may be limited by negative immunological checkpoints that attenuate immune responses. Recently a clinical trial of IL-15 in cancer immunotherapy was initiated. Finding strategies to conquer negative regulators and enhance efficacy of IL-15 is critical and meaningful for such clinical trials. In a preclinical study, we evaluated IL-15 combined with antibodies to block negative immune regulator cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in an established murine transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 prostate tumor model. IL-15 treatment resulted in a significant prolongation of survival in tumor-bearing animals. Coadministration of anti-PD-L1 or anti-CTLA-4 singly with IL-15 did not improve animal survival over that of IL-15 alone. However, simultaneous administration of IL-15 with anti-CTLA-4 and anti-PD-L1 was associated with increased numbers of tumor antigen-specific tetramer-positive CD8 T cells, increased CD8 T-cell tumor lytic activity, augmented antigen-specific IFN-γ release, decreased rates of tumor growth, and improved animal survival compared with IL-15 alone. Furthermore, triple combination therapy was associated with inhibition of suppressive functions of CD4+CD25+ regulatory T cells and CD8+CD122+ regulatory T cells. Thus, simultaneous blockade of CTLA-4 and PD-L1 protected CD4 and/or CD8 T-cell activity from these regulatory T cells. Combining the immune stimulatory properties of IL-15 with simultaneous removal of two critical immune inhibitory checkpoints, we showed enhancement of immune responses, leading to increased antitumor activity. [ABSTRACT FROM AUTHOR]
- Subjects :
- INTERLEUKIN-15
PROSTATE tumors
T cells
CANCER treatment
IMMUNOTHERAPY
PHYSIOLOGY
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 109
- Issue :
- 16
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 74470615
- Full Text :
- https://doi.org/10.1073/pnas.1203479109