| First Author | Yu P | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 16 | Pages | 6187-92 |
| PubMed ID | 22474386 | Mgi Jnum | J:183612 |
| Mgi Id | MGI:5319003 | Doi | 10.1073/pnas.1203479109 |
| Citation | Yu P, et al. (2012) Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model. Proc Natl Acad Sci U S A 109(16):6187-92 |
| abstractText | 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-gamma 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. |
