2152006 ). Furthermore, an elevated incidence of intratumoral Tregs and IL-17+ non-
Th17 cells are documented to be associated with poor outcome in oropharyngeal
carcinoma patients (Punt et al. 2016 ). Cytokines like IL-10 and TGF-β were reported
to let local naive T cells to convert into suppressor T cells and take advantage of the
suppressive functions of existing Treg cells (Ferris et al. 2006 ). The antigen present-
ing cells, DCs when exposed IL-10 encourage immunetolerance and CD4+ T cells
differentiation into suppressive Treg cells (Jonuleit et al. 2000 ). Another study illus-
trates that higher density of immature DCs and Treg cells and a lower density of
mature DCs and activated CTLs in metastatic head and neck cancer indicates an
immunosuppressive microenvironment which could be involved in the spread of
neoplastic cells to cervical lymph nodes (Gonçalves et al. 2013 ). Moreover, Quan
et al., reported that an adaptive immune response is driven by both mature, antigen-
experienced T and B cells within the microenvironment of oral carcinoma (Quan
et al. 2016 ). In HNSCC, the intratumoral cytotoxic CD8+ T cells were shown to
have increased expression of programmed death-1(PD-1), a surface protein that
blocks function of T lymphocytes. Moreover, programmed death ligand -1 (PD-L1)
expression is associated with augmented CD8+ T cell apoptosis (Cho et al. 2011 ).
Recent studies have emphasized the interaction between CSCs and immune system
in tumorigenesis of oral cancer. It is reported that CD44+ HNSCC cells showed
selective PD-L1 expression compared to CD44− cells leading to its decreased
immunogenicity which can be partially restored by inhibiting its expression (Lee
et al. 2016 ). Moreover, according to reports CD44+ HNSCC cells displayed
decreased HLA-A2 and TAP2 expression, the latter of which is indispensable for
assembling the MHC Class I-tumor antigen peptide complex suggesting that CSCs
in HNSCC may be less immunogenic than the bulk of the tumor cells (Chikamatsu
et al. 2011 ).
Among the microenvironment components, tumor-associated macrophages
(TAMs or tumor infiltrating macrophages) are the major inflammatory component
of the tumor which encourages tumor progression by prompting tumor invasion,
migration, and angiogenesis (Shieh et al. 2009 ). Usually, macrophages can be cat-
egorized into two distinct polarized states with opposite responses. The first one is
the classically activated pro-inflammatory (M1) state which possesses antitumor
activity whereas the second one is the alternatively activated suppressive (M2) state
which promotes tumor invasion and metastasis (Lúcio et al. 2016 ; Hu et al. 2016 ).
Accordingly, M1 TAMs participate in anti-tumor immune response via the produc-
tion of proinflammatory cytokines like INF- γ, IL-12, IL-23 (Sica et al. 2006 )
whereas M2 TAMs contribute to protumor immune response via the production of
various suppressive cytokines such as IL-10 and TGF-β and its accumulation near
blood vessels promotes angiogenesis (Martinez and Gordon 2014 ; Li et al. 2002 ;
El-Rouby 2010 ). The CD68 recognizes both tumoricidal M1 TAMs and anti-
inflammatory M2 TAMs while CD163 recognizes only M2 TAMs (He et al. 2014 ).
The substantial reports suggested a significant correlation between TAMs and poor
prognosis in patients with oral cancer (Lúcio et al. 2016 ). According to reports,
TAMs in oral SCC mostly possess a M2-like phenotype. Moreover, M2 TAMs
are documented to stimulate tissue remodeling and hinder anti-tumor cytotoxic
11 Oral Cancer Stem Cells Microenvironment