Researchers with UCLA’s Jonsson Comprehensive Cancer Center have discovered a way to amp up the power of killer T-cells, called CD8 cells, making them more functional for longer periods of time and boosting their ability to multiply and expand within the body to fight melanoma, a new study has found. When they programmed t-cells in the presence of IL-12 (Interleukin-12), they saw that the tumors decreased in size and the mice with brain metastases (cancer tumors) survived longer. In fact, Prins said that the mice treated with killer T cells primed in the presence of IL-12 lived about 2.5 times longer than those not receiving the IL-12.
The researchers tried to mimic the way the T cells in the immune system recognize and fight viruses in the body, stimulating what is called the innate immune system. The innate immune system is comprised of cells that immediately defend the body from infection and frequently is not stimulated in the presence of cancer, Prins said. However, the innate immune cells can be tricked into thinking a virus is present by treating with compounds that activate Toll-like receptors (TLR).
Prins’ group had previously demonstrated that TLR agonists, such as imiquimod, could synergize with dendritic cell vaccines, both in mouse models and patient clinical trials. Interleukin 12 (IL-12) is one of the predominant cytokines released when TLR are activated. In this study, they wanted to see how IL-12 would affect the CD8 T cells.
The optimal expansion, trafficking, and function of adoptively transferred CD8+ T cells are parameters that currently limit the effectiveness of antitumor immunity to established tumors. In this study, we addressed the mechanisms by which priming of self tumor-associated Ag-specific CD8+ T cells influenced antitumor functionality in the presence of the inflammatory cytokine IL-12. In vitro priming of mouse tumor-specific CD8+ T cells in the presence of IL-12 induced a diverse and rapid antitumor effector activity while still promoting the generation of memory cells. Importantly, IL-12–primed effector T cells dramatically reduced the growth of well-established s.c. tumors and significantly increased survival to highly immune resistant, established intracranial tumors. Control of tumor growth by CD8+ T cells was dependent on IL-12–mediated upregulation of the high-affinity IL-2R (CD25) and a subsequent increase in the sensitivity to IL-2 stimulation. Finally, IL-12–primed human PBMCs generated tumor-specific T cells both phenotypically and functionally similar to IL-12–primed mouse tumor-specific T cells. These results highlight the ability of IL-12 to obviate the strict requirement for administering high levels of IL-2 during adoptive cell transfer-mediated antitumor responses. Furthermore, acquisition of a potent effector phenotype independent of cytokine support suggests that IL-12 could be added to adoptive cell transfer clinical strategies in cancer patients.
Immunotherapy using dendritic cells (DCs) has the potential to activate both T cells and NK cells. We previously demonstrated the long-lasting antitumor responses by NK cells following immunization with bone marrow-derived DCs. In the current study, we demonstrate that long-term antitumor NK responses require endogenous DCs and a subset of effector memory CD4+ T (CD4+ TEM) cells. One month after DC immunization, injection of a tumor into DC-immunized mice leads to an increase in the expression of CXCL10 by endogenous DCs, thus directing NK cells into the white pulp where the endogenous DCs bridged CD4+ TEM cells and NK cells. In this interaction, CD4+ TEM cells express CD40L, which matures the endogenous DCs, and produce cytokines, such as IL-2, which activates NK cells. These findings suggest that DC vaccination can sustain long-term innate NK cell immunity but requires the participation of the adaptive immune system.
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