Helper T Cell Guides Killer Cells to Cancer
An important mechanism by which Melanoma cancer avoids antitumor immunity is by recruiting regulatory T cells (Tregs) to the tumor microenvironment. Recent studies suggest that suppressor Tregs and effector Th17 cells share a common lineage and differentiate based on the presence of certain cytokines in the microenvironment. Because IL-6 in the presence of TGF-β has been shown to inhibit Treg development and induce Th17 cells, they hypothesized that altering the tumor cytokine environment could induce Th17 and reverse tumor-associated immune suppression.
CTLA-4–B7 Interaction on the activated T-cell suppresses Th17 Cell Differentiation.Using anti-CTLA4 blocking antibody (Ipilimumab or tremelimumab) increases Th17 cells in peripheral blood of patients with metastatic melanoma. The Th17 cells can then migrate to the tumor's microenviroment. This sends the Danger Signal in the form of pro-inflammatory cytokines including IL-17. This is the third signal that is needed in the initiating of an immune response.
One of the mechanisms proposed is that CTLA-4 inhibition of T cell activation is due to antagonism of CD28-mediated costimulation. Both CD28 and CTLA-4 share the ligands B7.1 (CD80) and B7.2 (CD86); however, the affinity of the CTLA-4:B7 interaction is 10 times higher than the affinity of the CD28:B7 interaction. Although studies using CD28-deficient mice have shown that negative signaling through CTLA-4 is independent of CD28 expression, it is plausible that CTLA-4 interacts with B7 and prevents its interaction with CD28.
It is possible that T-cell activation can’t start until the level of CTLA-4 is block or decreased.
In my own experience, I did not get any activation until tremelimumab was introduced
If you Block the CTLA-4 and B7 with Ipilimumab or tremelimumab It will also take the brakes off the immune system and shift it towards activation.
I hypothesized that Th17 cells induce Th1-type chemokines, and in turn recruit Th1-type effector T cells into tumor microenvironment.
Recent data supports the notion that Th17 cells induce Th1-type chemokines through IL-17 and IFN- , and in turn recruit Th1-type effector T cells and NK cells into tumor microenvironment.
Increased tumor-associated IL-17 predicts improved patient survival
Mechanistically, Th17 cell–derived IL-17 and IFN- synergistically induced the production of CXCL9 and CXCL10, and in turn promoted effector T-cell migration toward tumor. The levels of CXCL9 and CXCL10 were directly correlated with tumor-infiltrating CD8+ T cells and NK cells. The data suggest that Th17 cells may play a role in promoting effector T-cell and NK-cell tumor trafficking and retainment, and the polyfuctional cytokine profile (IFN- +IL-17+) of Th17 cells is essential for synergistically inducing Th1-type chemokines.
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”