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INTRODUCTION
The immune system
plays an important role in the process of formation and further development of
tumor/cancer cells. The human body has a complete defense system that works in
an integrated manner to protect itself from various potential hazards including
the development of cancer cells. This mechanism is known as immunosurveillance
[1]. But on the other hand cancer cells also have various abilities to escape
from immunosurveilance activities. Among them is the ability of cancer cells to
induce dysfunction and apoptosis of CD8+ T-cells and increase the expansion of
regulator T-cells [2], express various immunosuppressive molecules that cause
microenvironmental conditions that are beneficial for the development of cancer
cells. In this context cancer cells have the ability to attract cells that can
inhibit the immune response to the area of tumor/cancer tissue [3], one of the
cells with potential immunosuppression is Treg cells (CD4+, CD25+, Foxp3+) [4].
Treg cells are reported to infiltrate tumor tissue in both humans and
experimental animals [5]. Treg cells inhibit the effectiveness of the immune
response to cancer cells so that it is an important target in cancer
immunotherapy. Reducing or inhibiting Treg cells is expected to increase the
effectiveness of the immune response to cancer [6,7].
Treg CELLS AND CANCER CELLS
Treg cells in the
blood circulation can be pulled towards the breast cancer area through various
pathways, including PGE2/EP2 (EP4), CCL22/CCR4, SDF1/CXCR4 and CCL5/CCR1 [8].
Cancer tissue microenvironment also plays an active role in increasing Treg
cell differentiation and expansion, CD4+ T-cells can be converted into Treg
cells in the presence of induction by TGF-β [9].
Treg cell activity
plays a role in influencing many components of the immune system, including
CD4+ (Th1, Th2 and Th17), CD8+, macrophage, dendritic cells (DCs), natural
killer (NK), NKT cells, mast cells, osteoblasts and B-cells [10], which
ultimately decreases and inhibits the immune response in the process of
eliminating cancer cells. Activated Treg cells suppress innate and adaptive
immune responses through various mechanisms, including: 1) Producing
immunosuppressive cytokines IL-10 and TGFβ; 2) Inhibiting maturation APC (in
this case dendritic cells) by inhibiting the expression of co-stimulator
molecules CD80/86 [11]; 3) Induces cytolysis of T-cells by releasing perforin
and granzyme which can kill cells CD4+, CD8+, dendritic cells and monocytes
[4,12]; 4) interferes with T-
With various immunosuppressive mechanisms,
Treg cells are an inhibitor of the success of anti-tumor immunity and
immunotherapy, so that Treg cells become an important target in cancer
immunotherapy. Reducing or inhibiting Treg cells is expected to increase the
effectiveness of the immune response to cancer, various strategies to inhibit
Treg cells have been studied in laboratory and clinical studies.
The strategy of inhibiting Treg cells can be
carried out on various pathways, including: 1) By depleting Treg cells
(quantitatively) with monoclonal antibodies to block IL-2 receptors [14]; 2)
Suppress/inhibit the function of immuosuppression through manipulation of the cytotoxic
T-lymphocyte antigen 4 pathway (CTLA-4) [15]; 3) Inhibits the homing process
[16]; and 4) Inhibits the process of differentiation and conversion of Treg
cells [17].
Therapy of various monoclonal antibodies that
suppress Treg cells shows significant results for the development of cancer,
but various side effects related to immunosuppression conditions become a
problem in patients. Among the side effects of monoclonal antibody therapy to
Treg cells are reported in various publications, including: 1) Treg cell
depletion is reported to increase the concentration of circulating IgM
autoantibodies [18]; 2) Blocking of CTLA-4 by ipilimumab can cause autoimmune
disorders in various organs called immune-related adverse events (IRAEs). IRAEs
can attack various organs and organs most affected are the skin and digestive
tract. Symptoms of IRAEs include: in the gastrointestinal tract in the form of
bowel perforation, enterocolitis, diarrhea, impaired liver function and in the
nervous system in the form of Guillain-Barre syndrome, and in the skin in the
form of rash and pruritus; 3) Anti-GITR monoclonal antibodies can cause
dangerous side effects, namely anaphylactic reactions.
Various side effects of monoclonal antibody
therapy require good anticipation efforts to prevent bad things in patients.
This encourages the thought of trying to explore natural materials with the
potential to inhibit Treg cells. Natural materials in general have a complex
composition because there are various components inside which can work synergistically
or antagonistically where the activity of an active ingredient can be
controlled by other active ingredients so that the use of natural materials in
a complex form is generally reported to be relatively safe.
THE EFFECT OF
TREATMENT OF PROPOLIS EXTRACT ON Treg CELLS
In past research we explored the effect of
giving Indonesian propolis extract to Treg cell populations in mice with breast
cancer models both in the number and activity of immunosuppressive molecule
expression (IL-10 and TGFb). The results showed that the treatment of propolis extract had no
significant effect on the population of Treg cells in quantity, but
significantly affected the Treg cell population that expressed TGFβ (CD4+,
CD25+, FoxP3+, TGFβ+) and Treg cell populations that express IL-10 (CD4+,
CD25+, FoxP3+, IL-10+) [19].
The effect of propolis extract on the
expression of IL-10 and TGFb has a positive immunological benefit in a
cancerous state because both are immunosuppressive cytokines synthesized by
Treg cells. IL-10 affects several mechanisms, including inhibiting dendritic
cell function by suppressing the production of inflammatory cytokines,
inhibiting MHC II, and expression of co-stimulator molecules [20,21]. IL-10,
known as cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory
cytokine that inhibits gene expression and synthesis of cytokines such as IFNγ,
IL-2, IL-4, IL-5, IL-13 and TNFa by T-cells and macrophages, inhibits antigen
presentation ability by reducing expression of MHC and B7 costimulatory
molecules on APC also inhibiting IFN menghambat synthesis by activated T cells
and peripheral blood mononuclear cells (PBMC) [21,22]. TGFβ can suppress the
systemic immune system, inhibit immunosurveillance and can affect immune cell
populations [23]. TGFβ also inhibits CTL activity, CD4+ T-cells, Macrophages,
dendritic cells, and NK cells that have an important role in tumor development,
also trigger the formation of Treg cells and Th17 cells [24]. TGF-β decreases
transcription of cytolytic and pro-apoptotic factors such as granzyme A and B,
perforin, interferon-γ and FAS ligands at both gene and protein levels, also
inhibits APC (antigen presenting cells) function which causes a decrease in
T-cell activation [25]. The Transforming Growth Factor-β also promotes tumor
development by increasing the escape mechanism of immunosurveillance, also in
the process of aTreg cell differentiation and conversion [17,26,27]. In serum
and breast cancer tissue, high levels of TGF-β are found and this is related to
a poor prognosis, in addition to metastatic breast cancer TGF-β expression is
higher than in primary tumors [28-30].
CONCLUSION
Propolis extract is a potential agent that is
useful for improving immune responses with the ability to reduce Treg cell
activity.
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