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by: theresa el-murr

Immunotherapel-murr-headshoteutic vaccines have emerged as a novel approach to treat cancer by upregulating the immune system to respond to tumor cells by various mechanisms including the stimulation of the adaptive and innate immune system. This stimulation is followed by cytokine secretion that leads to the recruitment and development of our body’s immune cells. One such cytokine, Interleukin-12, is an inflammatory cytokine that is secreted when it comes in contact with cancer cells and it activates key aspects of our immune system’s defenses. For example, IL-12 activates both T-lymphocytes (T-cells) of the adaptive system and natural killer cells of innate immunity. In addition, the presence of IL-12 induces the secretion of IFN-γ by natural killer (NK) cells and T-cells. By triggering the immune system to fight, the stimulation of IL-12 is a necessary step in the success of tumor immunotherapy.

One important job that IL-12 does is that it advances the development of CD4+ T helper cells, Th1 cells, from naïve T cells. Th1 cells are beneficial because these helper T cells secrete INF-γ, which stimulates the cell–mediated killing of cancer cells. Along with the stimulation of INF-γ, studies have shown that Th1 cells are necessary for the optimal development of effector CD8+ T-cells, also known as cytotoxic T lymphocytes (CTLs). These CTLs kill target cancer cells by secreting cytolytic enzymes, perforin, and granzymes. Along with helping to extinguish cancer cells, IL-12 helps T cells to become memory CD8+ T-cells to establish a memory in the immune system and prevent a subsequent relapse.murr-illustration

In addition to the benefits of IL-12 in our body’s adaptive immune system, our innate immune system can be involved as well. NK cells are part of our innate immunity and they produce cytokines such as INF-γ, TNF-α, and IL-10. NK cells lead to a positive feedback loop in which macrophages stimulate IL-12. Next, IL-12 stimulates NK cells leading to the production of INF-γ. Then, INF-γ stimulates macrophages to complete this cycle that results in an increase in the body’s NK cells, IL-12, and macrophages. This positive feedback loop is beneficial because activated NK cells cause the secretion of perforin and granzymes activating the apoptosis of cancer cells. Furthermore, according to Krebs et al., NK cell-mediated killing contributes to an increase in the adaptive immune response resulting in Th1 cells and the generation of CD8+ T cells.

As previously discussed, IL-12 is indispensable for eliciting responses to kill dangerous tumor cells, to create memory for tumor cells, and to start a feedback loop for the production of IL-12 and its helpers. Therefore, IL-12 secretion is needed to combat cancer. A mechanism for the provocation of IL-12 is through adjuvants in cancer vaccines. Adjuvants are molecules that stimulate the immune system and bind to pattern recognition receptors such as toll-like receptors (TLR). These toll like receptors recognize pathogen-associated molecular patterns such as cancer vaccine adjuvants. Certain TLRs, specifically TLRs 3, 4, and 8, are most important for inducing the release of IL-12, so it is imperative that adjuvants stimulate these receptors.

Currently, the Food and Drug Administration has approved multiple immunotherapeutic vaccines—a few preventative cancer vaccines that guard against infections from human papillomavirus, a hepatitis B virus, and a cancer treatment vaccine for metastatic prostate cancer called Sipuleucel-T. These cancer vaccines bolster the body’s ability to fight against invading cancer cells. Moreover, the stimulation of IL-12 by a vaccine will mount an efficacious innate, humoral, and cell-mediated effector defenses that are capable of abolishing tumors from the body while maintaining the memory to keep these tumors at bay. Thus, with more robust research targeting IL-12 in cancer vaccines, further exciting discoveries for tumor immunotherapy are within our grasp.

Theresa Josephine El-Murr is a second year pharmacy student at the McWhorter School of Pharmacy, Samford University, Birmingham, AL. Her research focuses on Immunotherapy and using novel formulation strategies to deliver tumor associated antigens to dendritic cells with Dr. Gary Bumgarner Ph.D and Dr. Bernadette D’Souza Ph.D.