Three major events must occur to induce CD8+ T cell–mediated, tumor-protective immunity against melanoma.
First, the T-cell receptor must be triggered by a (or multiple) self antigen–derived peptide MHC class I complex. Therefore, this event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells. Peripherally tolerant or “ignorant” self-reactive T-cell clones, once properly activated, may serve as tumor-specific effector T cells.
Second, simultaneously with T-cell receptor triggering, a distinct second costimulatory signal must be delivered, mediated by IL-2, B7-1, or B7-2, which engage IL-2 receptors and CD28 on the surface of the T cell, respectively (17). A source of these cofactors for effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts of IL-2, or by mature dendritic cells that display an increased level of B7-1/B7-2 costimulatory molecules on their cell surfaces.
Third, inflammatory cytokines, including IL-1, IL-6, IL-12, and IFN-γ provide a third signal that acts directly on T cells, referred to as the “danger signal”. This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells.1
The inflammatory cytokines act to promote T cell responses. They include IL-1, IL-6, IL-12, TNF-α, and IFN-g produced by macrophages and/or dendritic cells. Th17 cells also plays a part by secreting IL-17 and others. The most notable role of IL-17 is it involvement in inducing and mediating proinflammatory responses. Neutrophils are the earliest cells to arrive at the inflammatory site.
While TGF-β is a critical differentiation factor for Treg cells, IL6 completely inhibits the generation of Treg cells induced by TGF-β. Instead, IL6 and TGF-β together induce the differentiation of pathogenic Th17 cells. With IL-6 missing in the microenvironment, Treg Cells flourish.
If the CD4 + T cells differentiate into TH2 cells that produce IL-4, the other cells inhibited to produce IL-6. IL-4 was found to inhibit TNF-α and IL-1β by activated monocytes almost 100 %. The Secretion of IL-6 was decreased by approximatly 80 % in the presences of IL-4 Cytokine. TE Velde et al 1990
Neutrophil recruitment can also be induced by cytokines such as IL-17 and Tumor necrosis factor (TNF). Among the family of IL-17 cytokines, IL-17A and IL-17F are able
to promote the recruitment of monocytes and neutrophils via the induction of other cytokines and chemokines such as G-CSF and IL-8 by various cell types.
IL-17 appears to be involved in promoting neutrophil influx into the tumor site. With the influx of neutrophils in the tumor’s microenvironment and the inflammatory cytokines, capillaries at the melanoma tumor’s microenvironment become dilated, making room for the recruitment of immune cells.
Neutrophils also play an important role in promoting or suppressing the Th1 immune response, which is mediated partly by induction of cytokines or chemokines. Depending on the compositional makeup of the microenvironment, the neutrophils can promote the right immune response. Studies revealed that these neutrophils secreted three different chemokines. Some of these chemokines are known as chemoattractants. A chemoattractant is a chemical (chemotactic) agent that induces an organism or a cell, a leukocyte, to migrate toward.
These chemokines, MIP-1alpha, MIP-1beta, and MCP-1 are recently reported to serve as chemoattractants for Th1 cells. MIP-1alpha and MCP-1 are also reported to enhance antigen-specific (CTL) Cytotoxic T Lymphocyte induction. Studies revealed that MIP-1alpha /beta released from neutrophils are involved in recruitment of macrophages, T cells, monocytes, dendritic cells (DC), neutrophils and NK cells.
MIP-1 attracts predominantly CD8+ T cells while MIP-1 attracts CD4+ cells, although there is some overlap between subsets in response to both chemokines.
The other Chemokine MCP-1, binds to CCR2 to accumulate monocytes/macrophages, DC, T cells, and NK cells, thereby playing an important role in innate and adaptive immunity. CCR2 is Chemokine receptor that is key determinant of leucocyte trafficking.
IL-2 strongly upregulates expression of CCR2. With the MCP-1/CCR2 interface, the cells can traffic towards the tumor’s microenvironment. The trafficking of the cells and inflammatory cytokines present the perfect storm in the tumor’s microenvironment to induce the right immune response to eradicate the cancer, Melanoma.
Neutrophils circulate in the bloodstream and must be signaled to leave the bloodstream and enter tissues. The signal often comes from the bacteria themselves, from complement proteins, or from damaged tissue, all of which produce substances that attract neutrophils to a trouble spot. (The process of attracting cells is called chemotaxis.)
The combination of chemoattractants and inflammatory cytokines, in the tumor’s microenvironment, helps to send out a Danger Signal which in turn invokes the right immune response to eradicate the Melanoma tumors.
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B
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