Daniel S. Chen1,2#, Yoav Soen3#, Tor B. Stuge4, Peter P. Lee4, Jeffrey S. Weber5, Patrick O. Brown2,3, Mark M. Davis2,6*
1 Department of Internal Medicine/Division of Oncology, Stanford University, Stanford, California, United States of America, 2 Howard Hughes Medical Institute, Stanford University, Stanford, California, United States of America, 3 Department of Biochemistry, Stanford University, Stanford, California, United States of America, 4 Department of Medicine, Stanford University, Stanford, California, United States of America, 5 Norris Cancer Center, University of Southern California, Los Angeles, California, United States of America, 6 Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America
This is what I was looking for. It may hold the answer or could possibly point me in the right direction.
In the paper I came across a diagram that peaked my interest. It was a comparison between responders and non-responders.
They were looking at the cytokines secreted after the vaccine was given. When I saw what the cytokines were, I knew I was on the right track. These cytokines help in the differentiation of the CD4+ T-cells. What a find!!
Naïve CD4 T cells in the presence of TGF-b and IL-2 and others differentiate into Tregs.
TGF-b accelerates the CTLA-4 expression by stimulated CD4+ CD25- T-cells.
TGF-b requires CTLA-4 early after T-cell activation to induce FoxP expression generating CD4+ CD25+ Treg Regulatory cells.
The Th-17 cells produce IL-17. .IL-17 induces the production of many other cytokines (such as IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α).
So what was the non-responder missing, IL-6. With the missing IL-6, they weren’t able to produce Th-17 that secreted IL-17.
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
They were missing “The Danger Signal”.
Friendly inflammation “The Danger Signal”
Most of the time you have no notion of the microbial life-and-death struggle being waged within your body. At other times, though, you are acutely aware of the exact location of the battleground, thanks to the unmistakable signs of inflammation — heat, pain, redness, and swelling. Inflammation, the buildup of fluid and cells at the point of infection/cancer, is put into motion by cytokines — proteins that are released into the blood by the innate immune system when it encounters germs. Cytokines function like police dispatchers. They signal there's a problem, which activates the immune system's highway patrol force: the circulating lymphocytes of the adaptive immune system. These lymphocytes cruise the highways of the blood vessels and lymphatic system. In response to the chemical signal from the cytokines, increased blood flow rushes these circulating cells to the trouble spot.
“The CD8+ T-cell-mediated Immune Response to Eradicate the Tumors”
“Three major events must occur to induce CD8+ T cell–mediated, tumor-protective immunity against syngeneic 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. 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, IL-17 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.
The responder was able to produce inflammatory cytokines, including IL-1, IL-6, IL-12, IL-17 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 and invoke a robust immune response to the Melanoma Cancer.
“Our data altogether suggest the following model: Th17 cells go to the tumor site and, by secreting IL-17, activates residential cells to produce CCL2 and CCL20, which provokes the mobilization of DCs and other leukocytes to the tumor site. DCs uptake tumor antigens in the lung or tumor site and migrate to the lymph nodes where they activate CD8+ T cells against the tumor. The new wave of effector CD8+ T cells migrates back to the lung or tumor site and kills established tumors.
Therefore, our data demonstrating that Th17 cells and IL17 participate in antitumor immunity by facilitating T cell recruitment to the tumor site and CD8+ T cell priming and effector differentiation suggests a new avenue for developing Th17 cell-based therapy for tumors or chronic viral infections and as an adjuvant for vaccinations.”
(Dudley and Rosenberg, 2007; Rosenberg and Dudley, 2004)
Conclusion: We not only want to supress the Tregs, we also need to produce the "Danger Signal" to optimally activate TH1 differentiation and lead to clonal expansion of T cells to generate a robust tumor-specific immune response.
The Missing Link in T-cell activation using a Vaccine, "The Danger Signal"
“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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