Overexpression of interleukin‐15 in vivo enhances antitumor activity against mhc class I‐negative and ‐positive malignant melanoma through augmented NK activity and cytotoxic T‐cell response

Abstract

Key words: tumor immunity; IL-15; CTL; NK cells; transgenic miceInterleukin (IL)-15 is a 15 kDa cytokine 1,2 that uses ␤ and ␥ chains of the IL-2 receptor for signal transduction and shares many of the biologic activities of IL-2, including the induction of proliferation of phytohemagglutinin-stimulated normal PBMCs, NK cells and B cells and the generation of CTLs and lymphokineactivated killer (LAK) cells in PBMCs in vitro. [1][2][3][4][5][6][7] Memory phenotype CD8 ϩ T cells have also been shown to respond preferentially to exogenous IL-15. 8 Mice genetically lacking IL-15R␣ or IL-15 are deficient in NK cells, ␥␦ intestinal intraepithelial lymphocytes and memory phenotype CD8 ϩ T cells. 9,10 We have recently constructed transgenic (Tg) mice that express IL-15 cDNA encoding a secretable isoform of the IL-15 precursor protein under the control of an MHC class I promoter and that have an increased number of memory CD8 ϩ T cells in the peripheral lymphoid tissues. 11,12 The overexpression of IL-15 augmented the in vivo Tc1 responses to OVA and Toxoplasma gondii infection. [13][14][15] Recent studies using IL-15 Tg mice have shown increases in NK and memory CD8 ϩ T cells in the peripheral lymphoid tissues. 7,16 Taken together, the results suggested that IL-15 is important for the development and maintenance of not only NK cells but also Ag-specific CD8 ϩ T cells. Several studies using a murine model have suggested that IL-15 has antitumor effects. 17,18 Daily administration of IL-15 prolonged the period of remission induced by cyclophosphamide in mice bearing rhabdomyosarcoma. 19 We previously reported that treatment with IL-15 in combination with IL-12 enhanced the activities of NK and CD8 ϩ T cells in thoracic exudate cells, providing strong antitumor activity against malignant pleurisy. 20 We have also reported that tumor therapy based on IL-15 gene transfection was effective against Meth A tumor cells. 21 Thus, IL-15 may exert antitumor effects and be useful for cancer immunotherapy.The expression levels of MHC class I on malignant cells are important for determining the malignant and metastatic capacities of tumor cells. 22 MHC class I-expressing melanoma cells contain Ags able to activate cytotoxic CD8 ϩ T cells, although they are weakly immunogenic. [23][24][25] On the other hand, MHC class I-deficient melanoma is not destroyed by cytotoxic CD8 ϩ T cells but is susceptible to NK cells, 26 most of which express MHC class I-specific inhibitory receptors. 27,28 We report here that the tumor growth of both MHC class I-expressing and -deficient B16 melanoma cells is severely retarded in IL-15 Tg mice. The relative contributions of NK cells and cytotoxic CD8 ϩ T cells to antitumor activity in IL-15 Tg mice differs between these 2 melanoma cells. Overexpression of IL-15 may shed new light on a therapeutic approach to control tumors expressing a various range of MHC class I glycoproteins. MATERIAL AND METHODS Transgenic gene construction and generation of transgenic miceIL-15 Tg mice with C57BL/6 background, which w...

Soluble branched (1,4)‐β‐D‐glucans from Acetobacter species enhance antitumor activities against MHC class I‐negative and ‐positive malignant melanoma through augmented NK activity and cytotoxic T‐cell response

“…[30][31][32] It is widely accepted that MHC class I-negative tumor cells are susceptible to NK cells, while MHC class I-positive tumor cells are resistant to NK cells. 21,24,29 The results of the present study, however, showed that in vivo treatment with antiasialoGM1 Ab also abrogated the antitumor activity in AC-1-treated mice inoculated with MHC class I-positive B16 K b cells. Although B16 K b melanoma cells express MHC class I molecules on their surfaces, the level of MHC class I expression of the tumor was shown to be significantly lower than those of tissue cells (Fig.…”

NK Dendritic Cells Expanded in IL-15 Exhibit Antitumor Responses In Vivo

“…IL-15 has also been implicated in the augmentation of NK cell cytotoxicity and IFN-␥ secretion (9,11). Additionally, IL-15-transgenic mice have been found to be more resistant to tumors (21). The effects of IL-15 on the development, homeostasis, survival, and activation of NKDC are unknown.…”

An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site

“…The antitumor potential of IL-15 was observed in mouse models employing recombinant IL-15 (16,17), antibody-IL-15 fusion protein (18), IL-15 gene-modified tumor cells (19,20), and IL-15 transgenic mice (21). The relevance of IL-15 trans-presentation for an efficient antitumor response was shown in a mouse model with IL-15Ra-transfected MC38 tumor cells.…”