Augmented interleukin (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

摘要

Interleukin-15 (IL-15) has potential as an immunotherapeutic agent for cancer treatment because it is a critical factor for the proliferation and activation of natural killer (NK) and CD8⁺ T cells. However, monotherapy of patients with malignancy with IL-15 that has been initiated may not be optimal due to limited expression of the private receptor, IL-15Rα. We demonstrated greater CD8 T-cell mediated therapeutic efficacy of a combination regimen of murine IL-15 (mIL-15) administered with an agonistic anti-CD40 antibody (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-100% 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 mIL-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 that in wild type mice. The combination regimen significantly increased the numbers of TRAMP-C2 tumor specific SPAS-1/SNC9-H8 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 (BMDCs), 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.