Augmented IL-15Rα expression by CD40 activation is critical in synergistic CD8 T cell-mediated antitumor activity of anti-CD40 antibody with IL-15 in TRAMP-C2 tumors in mice Journal Article
| Authors: | Zhang, M.; Ju, W.; Yao, Z.; Yu, P.; Wei, B. R.; Simpson, R. M.; Waitz, R.; Fassò, M.; Allison, J. P.; Waldmann, T. A. |
| Article Title: | Augmented IL-15Rα expression by CD40 activation is critical in synergistic CD8 T cell-mediated antitumor activity of anti-CD40 antibody with IL-15 in TRAMP-C2 tumors in mice |
| Abstract: | IL-15 has potential as an immunotherapeutic agent for cancer treatment because it is a critical factor for the proliferation and activation of NK and CD8 + T cells. However, monotherapy of patients with malignancy with IL-15 that has been initiated may not be optimal, because of the limited expression of the private receptor, IL-15Rα. We demonstrated greater CD8 T cell-mediated therapeutic efficacy using a combination regimen of murine IL-15 administered with an agonistic anti-CD40 Ab (FGK4.5) that led to increased IL-15Rα expression on dendritic cells (DCs), as well as other cell types, in a syngeneic established TRAMP-C2 tumor model. Seventy to one hundred percent of TRAMP-C2 tumor-bearing wild-type C57BL/6 mice in the combination group manifested sustained remissions, whereas only 0-30% in the anti-CD40-alone group and none in the murine IL-15-alone group became tumor free (p < 0.001). However, the combination regimen showed less efficacy in TRAMP-C2 tumor-bearing IL-15Rα -/- mice than in wild-type mice. The combination regimen significantly increased the numbers of TRAMP-C2 tumor-specific SPAS-1/SNC9-H 8 tetramer +CD8 + T cells, which were associated with the protection from tumor development on rechallenge with TRAMP-C2 tumor cells. Using an in vitro cytolytic assay that involved NK cells primed by wild-type or IL-15Rα -/-bone marrow-derived DCs, we demonstrated that the expression of IL-15Rα by DCs appeared to be required for optimal IL-15-induced NK priming and killing. These findings support the view that anti-CD40-mediated augmented IL-15Rα expression was critical in IL-15-associated sustained remissions observed in TRAMP-C2 tumor-bearing mice receiving combination therapy. |
| Keywords: | controlled study; protein expression; cancer combination chemotherapy; drug efficacy; drug potentiation; nonhuman; cd8+ t lymphocyte; animal cell; mouse; animal tissue; dendritic cell; protein protein interaction; animal experiment; animal model; antineoplastic activity; in vitro study; wild type; drug mechanism; antigen specificity; prostate tumor; drug response; protein induction; drug cytotoxicity; bioluminescence; t lymphocyte activation; interleukin 15; cd40 antigen; cd40 ligand monoclonal antibody; interleukin 15 receptor alpha |
| Journal Title: | Journal of Immunology |
| Volume: | 188 |
| Issue: | 12 |
| ISSN: | 0022-1767 |
| Publisher: | The American Association of Immunologists, Inc |
| Date Published: | 2012-06-15 |
| Start Page: | 6156 |
| End Page: | 6164 |
| Language: | English |
| DOI: | 10.4049/jimmunol.1102604 |
| PROVIDER: | scopus |
| PMCID: | PMC3370156 |
| PUBMED: | 22593619 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 30 August 2012" - "CODEN: JOIMA" - "Source: Scopus" |
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