As I research why some patients respond to therapies i.e. vaccination and other immunotherapy and others don’t, I ask WHY? In my quest to get the answer or answers, I came across a paper called “Marked Differences in Human Melanoma Antigen-Specific T Cell Responsiveness after Vaccination Using a Functional Microarray”.
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.
We concluded from these studies
that IL-1 and perhaps IL-6 play a critical role in the differentiation and expansion
of Th17 cells. Yoshihiro Miyahara et al
IL-6 controls Th17 immunity by inhibiting the conversion
of naive CD4+ T cells into Foxp3+ regulatory T cells.
Using in vitro and in vivo approaches, we determined that
under neutral conditions, simultaneous activation of Tregs and naive
CD4+ conventional T cells in the presence of APCs resulted
in conversion of Tregs into IL-17–producing cells, and endogenous
IL-1β was mandatory in this process according to Vassiliki A. Boussiotis et al. “IL-1β–Mediated Signals Preferentially Drive
Conversion of Regulatory T Cells but Not Conventional T Cells into
IL-17–Producing Cells”
IL-6 protects CD4 T
cells from cell death but also inhibits the suppressive effect of T regs.
“Thus, the addition of IL-6 to the tumor
microenvironment skews the balance toward Th17 cells in a murine
model of pancreatic cancer. The delayed tumor growth and improved
survival suggests that induction of Th17 in the tumor
microenvironment produces an antitumor effect.” David
C. Linehan et al
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 approximately 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 provides 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.
Conclusion: Based on
my observation, the cytokine that ties this “Danger Signal” to the immune
system is IL-6.
- IL-6 protects CD4 T cells from cell
death but also inhibits the suppressive effect of Tregs.
- IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4+ T cells into Foxp3+ regulatory T cells.
So
what is causing the lack of IL-6 in the non-responders? The IDO enzyme. This enzyme catalyzes the degradation of the
essential amino acid L-tryptophan to N-formylkynurenine.
IDO enzyme
degrades tryptophan and through the GCN2 kinase pathway inhibits the
transcription of IL-6. Without the transcription of IL-6, the IL-6 cytokine
cannot be produced leading to the T-cell differentialtion toward the T
Regulatory cell instead of the TH17 phenotype.
My
guess is the tumor induced enzyme called IDO may the Missing Link to intiating an
immune response.IDO produced by Tumor
cells significantly inhibited interleukin (IL-2) expression and proliferative
response in T-cells and increased apoptosis (death) of T-cells. Tryptophan depletion is known to halt cell cycle progression by triggering
the antiproliferative GCN2 pathway in lymphocytes.
Also, IDO is upregulated in antigen-presenting dendritic cells (DC) by autocrine
IFN-γ released as a result of Treg cell–induced CTLA-4/B7-dependent
cell-cell signaling.
It is well established that IDO expression
by APCs or tumors can inhibit immune responses.
Tryptophan depletion by IDO-expressing
tumors is a common mechanism of immune evasion inducing regulatory T cells and
inhibiting effector T cells.
So adding IDO inhibitor to a combinatorial therapy like Yervoy for melanoma
cancer should see a synergist response.
Bristol Myer Squibb and Incyte Corporation are following this Science along
Newlink.
“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
