Tumor Cells Engineered with IL-12 and IL-15 Genes Induce Protective Antibody Responses in Nude Mice

Abstract

IL-12 and IL-15 stimulate T, B, and NK cell functions through independent mechanisms, and cooperative effects of these cytokines have been reported. The human MHC class I-negative small cell lung cancer cell line, N592, genetically engineered to secrete IL-15, N592/IL-15, showed a reduced tumor growth rate, while N592 cells engineered with IL-12, N592/IL-12, grew similarly to the wild-type N592, N592 parental cells (N592pc), in nude mice. However, N592 cells coexpressing both cytokines, N592/IL-12/IL-15 cells, were completely rejected by 100% of nude mice. Here we show that 60% of nude mice rejecting N592/IL-12/IL-15 cells were resistant to N592pc rechallenge. SCID mice rejected N592/IL-12/IL-15 cells, but did not develop resistance to N592pc rechallenge, suggesting a role of Ab responses. Among nude mice rejecting N592/IL-12/IL-15 cells, those developing resistance to N592pc rechallenge had significantly higher titers of anti-N592 IgG2b Abs than nonresistant nude mice. Induction of an Ig class switch in nude mice was related to the expression of IFN-γ and CD40 ligand in the draining lymph nodes. An IgG2b, anti-N592 mAb, derived from N592/IL-12/IL-15-immunized nude mice splenocytes induced significant protection against N592pc, while an IgM mAb was ineffective. The protective IgG2b mAb, but not the IgM mAb, triggered Ab-dependent cell-mediated cytotoxicity by nude mouse splenocytes against N592pc. These data indicate that IL-12 and IL-15 synergistically trigger innate, immunity-mediated, anti-tumor effects, resulting in cytotoxic IgG Ab responses in T cell-deficient mice. Protective Ab responses may relate to both direct actions of IL-12 and IL-15 on B cells and to the activation of an innate immunity-B cell cross-talk.

Interleukin-15 Enhances Innate and Adaptive Immune Responses to Blood-Stage Malaria Infection in Mice

“…Accordingly, the most effective vaccination strategies are those that trigger early and strong IFN-␥ production, which in turn induces long-lasting, IFN-␥-mediated protective immunity. Although, on its own, IL-15 is not essential for IFN-␥ and antibody production, the results presented in this study and by other investigators (19,28,30) demonstrate the benefit of IL-15 as an adjuvant to induce maximal IFN-␥ and antibody responses. The potential for IL-15 use in vaccine systems will necessitate further studies that examine how IL-15 interacts with other factors in the complex cytokine network to orchestrate protective immune responses to Plasmodium parasites.…”

Prolonged, NK Cell-Mediated Antitumor Effects of Suicide Gene Therapy Combined with Monocyte Chemoattractant Protein-1 against Hepatocellular Carcinoma

“…NK cells are a part of the innate immune system, a first-line defense against tumor cells, and exert antitumor effects of NK cells rapidly without any prior sensitization (46). The depletion of NK cells has been shown to promote metastases or tumor growth after rechallenge with primary tumor cells (15,44,47). We demonstrated here that the growth of rechallenged parental tumor cells or newly challenged heterologous tumor cells was suppressed after eradication of the primary tumors.…”

“…Moreover, nude mice have limited populations of extrathymically matured T lymphocytes, including ␥␦ T cells (52), and these may be reduced slightly by treatment with AGM1 Ab (53). Both NK cells and V␦1␥ ␦T lymphocytes have been reported to prevent the growth of s.c. melanoma cells, with both cell types detected at the sites of the s.c. tumors (47). Therefore, we cannot exclude the possibility that the memory subset of ␥ ␦T cells affects antitumor immunity against homologous and heterologous cells, thus leading to differences in the magnitude of tumor suppression.…”

The redox state of the lung cancer microenvironment depends on the levels of thioredoxin expressed by tumor cells and affects tumor progression and response to prooxidants

“…Two ×10 6 cells from the different cell clones, maintained in the growth phase, were subcutaneously injected into the flanks of groups (6/group) of 6‐ to 8‐week‐old SCID ( scid/scid ) mice (Charles River, Lecco, Italy) and tumor formation was monitored. The wider and smaller diameters of subcutaneous tumors were measured by a caliper and were used for calculating the tumor growth area 35. Statistical analysis was performed by the Mann‐Whitney test; p < 0.05 values were considered as significant.…”