Murine B16 Melanoma Vaccination-Induced Tumor Immunity: Identification of Specific Immune Cells and Functions Involved

Abstract

Vaccination using inactivated B16 melanoma cells that have been treated in vitro for > 2 weeks with interferon-alpha (IFN-alpha) (B16alpha cells) has been shown to elicit a protective host antitumor immunity. In these studies, vaccination with B16alpha cells has been shown to provide protection against primary B16 tumor challenge, established B16 tumors, and metastatic B16 tumors. Specific immune cells and factors that might mediate this tumor immunity have now been evaluated. Macrophage depletion studies suggest that macrophage function is required for expression of tumor immunity either for processing of antigen or for cytokine production but that macrophage function is not involved in direct cytotoxicity against the B16 challenge tumor. CD8(+) T cell depletion studies show that cytotoxic T cell function is required for expression of tumor immunity. Syngeneic knockout mouse experiments offer further insights into the immune cells and factors that mediate the development and expression of tumor immunity. First, interleukin-12 (IL-12) knockout mouse experiments identify IL-12 as an important cytokine in mediating the development of tumor immunity. Second, specific knockout mouse experiments show that tumor immunity requires the function of CD4(+) T cells, CD8(+) T cells, and natural killer (NK) cells. Third, specific knockout mouse experiments show that tumor immunity does not require the function of B cells. The results suggest that vaccination with inactivated B16alpha cells induces an active, cell-mediated immunity to B16 melanoma cells. The tumor vaccination protocol with B16alpha cell vaccinations establishes a potent tumor immunity against B16 melanoma tumors in mice and may serve as a model for induction of tumor immunity against primary or secondary melanoma tumors in humans.

Activated natural killer cell-mediated immunity is required for the inhibition of tumor metastasis by dendritic cell vaccination

“…Similar findings, which show that IL-12 has an effect on NK cell activation, were recently reported in a highly immunogenic rat histiocytic tumor (Alli and Khar, 2004). Indeed, vaccination with inactivated B16 melanoma cells showed that IL-12 is an important cytokine in mediating the development of tumor immunity (Wu and Fleischmann, 2001). It has also been shown that DCs expressing IL-12 confer NK-mediated tumor protection, and that NK activation depends on both DC-NK cellular interaction and IL-12 secretion (Miller et al, 2003).…”

Tumor vaccine composed of C-class CpG oligodeoxynucleotides and irradiated tumor cells induces long-term antitumor immunity

“…These results suggested that the repeated vaccination was more effective in generating a durable antitumor response than a single vaccination. Similarly, in the study of Wu and Fleischmann, it was reported that after repeated vaccination of mice with a tumor vaccine (composed of irradiated B16 melanoma cells exposed in vitro to long-term IFN-alpha treatment) a protective durable immunity against a second tumor challenge was significantly increased [21,22]. Our results are also in agreement with the statements of other authors that short-term or weak antigen stimulation can trigger the initial proliferation of effector T cells but is insufficient to trigger the long-lived memory T cells [23-25].…”

Cisplatin primes murine peritoneal macrophages for enhanced expression of nitric oxide, proinflammatory cytokines, TLRs, transcription factors and activation of MAP kinases upon co-incubation with L929 cells

“…Usually, interaction with pathogens/tumor cells leads to macrophage activation, inducing the production of NO and release of proinflammatory cytokines such as TNF-a, IL-1b, IL-12 and IFN-g (Zembala et al, 1993, 1994; Shrivastava et al, 1995;Wu and Fleischmann, 2001). The activation of macrophages and the achievement of tumoricidal state is a multistep event involving cell-to-cell contact and elaboration of cytotoxic effector molecules like NO and proinflammatory cytokines (Fan et al, 2002;Chen et al, 2003).…”

“…Many studies have shown that activated macrophages selectively lyse tumor cells in vitro (Fan et al, 2002;Chen et al, 2003) and play an important role in the immune-mediated destruction of tumor cells in vivo (Bonnotte et al, 2001;Tsung et al, 2002). Macrophages on co-incubation with tumor cells become activated and acquire tumoricidal capacity, a process that is an outcome of expression of one or more cytotoxic effector molecules such as peroxidase, cytolytic proteases, nitric oxide (NO) and a variety of proinflammatory cytokines (Zembala et al, 1993(Zembala et al, , 1994Shrivastava et al, 1995;Wu and Fleischmann, 2001). The signal transduction mechanisms of macrophages in relation to their activation with LPS, cytokines, CP, thymocin-a, MCP-1, etc., have been well worked out (Shishodia et al, 1998;Biswas and Sodhi, 2002;Paul and Sodhi, 2002).…”