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.

• Authors: Meili Zhang, Wei Ju, Zhengsheng Yao, Ping Yu, Bih-Rong Wei, R Mark Simpson, Rebecca Waitz, Marcella Fassò, James P Allison, Thomas A Waldmann
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 188 Issue 12 Pg. 6156-64 (Jun 15 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22593619 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• CD40 Antigens
• Interleukin-15
• Interleukin-15 Receptor alpha Subunit

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• CD40 Antigens (immunology, metabolism)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Dendritic Cells (immunology, metabolism)
• Flow Cytometry
• Interleukin-15 (administration & dosage)
• Interleukin-15 Receptor alpha Subunit (biosynthesis, immunology)
• Killer Cells, Natural (immunology, metabolism)
• Lymphocyte Activation (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasms, Experimental (drug therapy, immunology, metabolism)