|PTGS2; Dendritic Cell; Immunity; Cancer
|KO: Knockout; KD: Knockdown; DC: Dendritic Cell; MDCC:
Myeloid Derived Suppressor Cell; CD: Cluster of Differentiation; MHC:
Major Histocompatibility Complex; MMP: Matrix Metalloproteinase
|Dendritic cells (DC) are a special type of leukocytic immune
sentinel able to aware the immune system for the presence of infections
and play a central role in the initiation of both innate and adaptive
immune responses [1-3]. Nowadays, DC isconsidered as potential
candidate for vaccine preparation against cancer and autoimmune
diseases [4-5]. Cox2 dampen the immune function of several immune
cells including dendritic cell [6-7]. Increased amounts of COX2 are
commonly found in both premalignant tissues and malignant tumors
such as lung, breast, prostate, ovary, head, neck, skin, and colorectal
cancer [8-20]. As a potential inducers of oncogenes, growth factors,
and tumor promoters, COX2 affects many processes involved in
carcinogenesis, therefore become an attractive therapeutic target. It
induces xenobiotic metabolism, angiogenesis, apoptosis, inflammation,
immunosuppression, and invasiveness . While ample clinical and
experimental data support the critical role of COX2 inthe prevention
of cancer [13-20], the therapeutic strategy to inhibit PTGS2 in DC to
prevent cancer remain to be clarified. Therefore, understanding the
mechanism how PTGS2 prevent cancer via DC mediated immunity is
a matter of utmost importance.
|PTGS2/COX2 is highly induced in different types of cancerous cell
and promotes cancer in diverse animals [22-25]. Previous studies have
shown that PTGS2prompt cancer by inducing immunosuppressive
environment [26,30]. Recently, it has been shown that, PTGS2 decrease
the immune function of T-cell by expressing Foxp3 . Interestingly,
PTGS2found to be highly induced in dendritic cell. DC are present
in the processed antigen , stimulate T-cell to maintain constant
immune protection against foreign antigen. PTGS2 highly induced in
DCto prevent the immunostimulatory capacity [29-30] and the DC
highly express PTGS2are unable to stimulate T-cell against cancer.
Interestingly, when COX2 expression dampens or reduces by any
means (such as, pharmacological inhibition, KD, KO) from DC, it restores the capacity to stimulate T-cell against cancer and several
experiments show that when PTGS2 inhibitor used in DC it can
prevent cancer compared of wild type DC [29,30].
|High expression of PTGS2 suppresses the immune function of
DCthrough the production of several immunosuppressive steroids
metabolites such as, PTGS2 like PGG2, PGE2, and PGH2 . PGE2
is the main culprit from them who made the immunosuppressive
environment by expressing FOXp3 in DC and these types of DC
ultimately fails to stimulate T-cell. Again excessive expression of
PTGS2 leads to huge secretion of immunosuppressive cytokines IL10
 and maintain immune suppressive tumor microenvironment to
protectthe tumor cell and reduce the stimulatory capacity of DC and
at the same time prevent the pro-inflammatory cytokine secretion,
responsible for T-cell stimulation.
|Simultaneously, high amount of PTGS2 produce excessive
PGE2 that’s enhances production of MDCC (Myeloid derived DC)
to suppress immune response . Usually, immature DC shows
lower level of MHC and co-stimulatory molecules whereas mature
DC hasincreasedlevel of MHC and costimulatorymolecules .
However, inhibition of PTGS2 from immature DC greatly increases
the costimulatory molecules CD86 and CD80 and also MHC I and
MHC class II in contrast to wild type DC . The similar results
in wild type of DC have been reported even after stimulation with
lipopolysaccharide (mDC) compare to cox2 inhibitor treated DC.
|PTGS2expression dampens the migration and invasion capacity
of DC. It is reported that cox-2 expression enhances the activation of proteolytic enzymes such as matrix metalloproteinase 2 (MMP-2) and
MMP-9 and thereby increase lymphovascular invasion of cancer cell
 and may be it also associated with migratory chemokines CCR7 up
regulation in DC. Taken together, these observations suggest that the
presence of COX2 appears to play a critical role in tumor cell migration
and invasion.When wild type DC culture with T-cell it also reduces
the secretion of tumor lysis cytokine INFγ and some studies revealed
that PTGS2 silenced DC strongly enhance INFγ  to destroy cancer
cell. Together these data suggest that PTGS2 act as a negative immune
regulator of DC.
|PTGS2 expression exaggerates cancer condition by proliferation,
differentiation and migration of cancer cell and creates an effective
immunosuppressive condition to immune cells. When PTGS2 induces
in DC it gives negative effects on DC proliferation, differentiation and
maturation. Silencing of PTGS2 by any means enhances DC immunity
and T-cell stimulation capacity by increasing the level of MHCs and
co-stimulatory molecules, secretion of immunostimulatory cytokines
(IL12, INfγ) and reduction of immunosuppressive cytokine IL10 and
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