the vast majority of cancers in the oral cavity are squamous cell carcinomas ( scc)its evolution is influenced by host immune response cells ( e.g. , cd8 t ,   cd4 t , natural killer cells - nk , dendritic cells - dc , macrophages , and eosinophils ) .   
the eosinophils are considered as destructive effector leukocytes with cytotoxic activities mainly implicated in parasitic infections ( e.g. , helminthic infections ) and allergic diseases ( e.g. , bronchial asthma , allergic dermatitis , etc . ) .
however , studies have shown that they can also be involved in tissue remodelling and in innate and acquired immunity response modulation [ 2 , 3 ] ( figure 1 ) .   under diverse stimuli ( e.g. , infections , tumours , etc .
) , the eosinophils are able to release different substances , such as , eosinophil cationic protein ( ecp ) , major basic protein ( mbp ) , eosinophil peroxidise ( epo ) , eosinophil - derived neurotoxin ( edn ) , il-1 , il-2 , il-4 , il-5 , il-6 , il-8 , il-10 , il-12 , il-13 , il-18 , interferon ( inf)- , tumor necrosis factor ( tnf)- , transforming growth factor ( tgf)- , tgf- , chemokines ( rantes , endotaxin-1 ) , platelet - activating factor ( paf ) , leukotriene c4 ( ltc4 ) , neuromediators , and indoleamine 2,3-dioxygenase ( ido ) [ 4 , 5 ] .
these substances may cause cell death and induction of inflammatory symptoms as well as contribute to tumour progression or regulation .
furthermore , the eosinophils present membrane receptors ( e.g. , il-1 , 3 , 4 , 5 , 8 , 10 , 12 , 13 , granulocyte monocyte colony - stimulating factor 
gm - csf , ifn- , tnf- , and macrophage inflammatory protein-1 ) that confer a survival and recruitment capacity of eosinophils themselves .   in oral scc ,
several studies have shown that eosinophils can be associated with an improved prognosis , but there are other studies however , showing their association with a poor prognosis as well [ 6 , 7 ] . in this short review ,
we summarize briefly the role of the eosinophils in the general context of immunoregulation and its relation with oral squamous cell carcinoma .
under a specific stimulus , the nave cd4 t and cd8 t cell can be differentiated , respectively , into th2 and tc2 cells and secrete mainly cytokines involved with humoral immunity such as il-4 , il-5 , il-10 , and il-13 [ 8 , 9 ] .   the initial recruitment and activation of eosinophils towards the tumour microenvironment is principally related with th2 response , although necrotic cells can stimulate both the migration and the activation of eosinophils [ 10 , 11 ] . according to the literature
, th2 response may eliminate the cancer on the dependence of eosinophils and macrophages [ 8 , 1214 ] .
il-4 and il-13 are potent inducers of eotaxin chemokines that can explain the eosinophilia associated with th2 responses .   in oral squamous cell carcinoma ,
the eotaxin expressed by tumour cells and eosinophils were involved in the mechanisms of eosinophil chemotaxis to the tumour .  
.   il-13 has also been involved with the antitumour immune response mediated mainly by neutrophils ( gr-1 ) and macrophages ( mac-3 ) .  
however , il-13 can also inhibit the ifn- secretion and cd8 cytotoxic t lymphocyte ( ctl ) activity and compromise the anti - tumour immunity response .   
studies have also shown that eosinophils can process and present histocompatibility complex ii ( mhc - class ii ) molecules   and polarize the th2 response . upon stimulation with ifn- , il-3 , and gm - csf , human eosinophilc cell line differentiated with dibutyryl cyclic amp ( deol-1 ) and human peripheral blood ( pb ) eosinophils were able to respond to the lymphoid chemokines ( e.g. , ccl11 , ccl21 , and ccl25 ) .
in addition , cytokine - stimulated deol-1 cells expressed human leukocyte antigen ( hla)-dr and costimulatory molecules such as cd80 , cd86 and cd40 .
therefore , eosinophils can migrate to the lymphoid chemokine microenvironment and express antigen - presenting cells ( apcs)- related costimulatory molecules .
however , some experimental models have suggested that eosinophils are inefficient antigen - presenting cells when compared to macrophages   or dendritic cells .  
the eosinophil - derived neurotoxin stored in eosinophils granules is able to induce dc maturation and activation through up - regulation of mitogen - activated protein ( map ) kinases , nuclear factor - kappa b ( nf kappa b ) and cd83 , cd86 costimulatory molecules , and mhc class ii expression [ 27 , 28 ] .  
edn - treated human dcs stimulated th2 immune response via toll - like receptor ( tlr)2-myd88 signal .  
they may express ifn- as well as il-4 , il-5 and il-10 suggesting a subpopulation of human eosinophils that expresses th1 or th2 cytokines , respectively .
it has been shown that not only the th1 response is able to eradicate the tumour through the cellular immunity response but also th2 response via tumour necrosis .
contrarily , eosinophils are capable to downregulate the antitumour immunity , through mainly il-10   and ido production . il10 is a potent inhibitor of mhc complex and cd80 and cd86 expression on dc as well as it suppresses the dc differentiation .
contrarily , il-10 can play a role in the b cell activation and survival .   through indoleamine
this enzyme catalyzes the amino acid tryptophan to kynurenine which is able to cause cycle arrest and apoptosis from uncommitted cd4 t cells   as well as maintenance of th2 response .
the ido was correlated with the poor prognosis in the non - small cell lung cancer .  
it has been shown that the eosinophils are capable of producing various substances ( e.g. , vascular endothelial growth factor - vegf , fibroblast growth factor - fgf , tnf- , gm - csf , nerve growth factor - ngf , tgf- , and il-8 ) that can promote angiogenesis and produce collagenous fibers .
in head and neck scc , it has been shown that the th1 response is mainly associated with a better prognosis than those with the th2 response [ 38 , 39 ] .   according to argarwal and colleagues , early stage of oral scc
expressed mainly inf- and il-2 genes ( th1 responses ) , whereas the advanced stage tumours presented il-4 and il-10 expression ( th2 response ) .
in addition , advancing lesions of the tongue squamous cell carcinoma , induced by 4-nitroquinoline-1-oxide , have downregulated th1-type and upregulated th2-type cytokine production .  
regarding studies with eosinophils in the blood , the presence of eosinophils and th2 cells can be related with tumour progression   and poor prognosis [ 43 , 44 ] .  
peripheral blood analyses of intraoral squamous cell carcinoma with a history of tobacco use presented enhanced expression of th2 cytokine .
however , patients with malignant disease ( e.g. , acute lymphoblastic leukemia , acute myelogenous leukemia ) that underwent stem cell transplantation   or patients with cervical cancer treated with whole - pelvic irradiation   presented increased blood eosinophilia and better overall survival .
tumour - associated tissue eosinophilia ( tate ) has been reported in diverse sites [ 14 , 35 , 4753 ] including the head and neck region [ 6 , 7 , 5465 ] ( figure 2 ) .   in the head and neck region ,
some studies have shown that the tate has a favourable prognosis , suggesting that eosinophils may play a protective role against epithelial tumours [ 6 , 55 , 60 , 62 ] .
other studies however , suggest that eosinophils may play a role in promoting epithelial tumour growth accounting for a poor prognosis [ 7 , 57 , 58 ] or even no effect on tumour evolution [ 54 , 56 , 59 , 63 ] . with regard to good prognosis
, it has been shown that oral scc patients with tate presented higher overall survival   and less incidence of distant metastasis in head and neck tumours .
nevertheless , tadbir and colleagues   have shown that tate was not associated with vascular , perineural , muscle invasion , and locoregional metastasis in scc of the oral cavity .
similar results were observed in nasopharyngeal carcinoma   and oral ssc   where the eosinophils were not associated with local recurrence , distant metastases , or survival . in another study of laryngeal squamous cell carcinoma ,
tate was associated only with the age - tate - positive patients presented between 50 and 60 years of age , whereas the tate - negative patients were between 60 and 70 years of age . according to oliveira and colleagues   and cormier and colleagues , the presence of eosinophis in damaged striated muscular fibers of oral cancer or in capsule of b16-f10 melanoma cell - derived tumours , respectively , could be related with tissue remodelling .    on the other hand , the presence of eosinophils has also been related with a poor prognosis . in oral scc ,
eosinophilic infiltration and hla - dr expression in tumour cells were related to unfavourable prognosis . in the experimental studies of oral carcinoma
, the depletion of tate with anti - il-5 mab was associated with a delayed development of the tumours . according to falconieri and colleagues   and oliveira and colleagues , the eosinophil presence in the scc of the oral cavity
similar results have been observed in head and neck carcinoma [ 57 , 58 ] and cervix   where eosinophils infiltrate has increased the suspicion of invasion .
the presence of > 3 eosinophils / high - power field ( hpf ) , 5/hpf , and 10/10  hpf in cervical incisional biopy and excisional specimens were associated with invasion .   according to dorta and colleagues ,
the prognosis related with tate is controversial due to the different methodology utilized to count tumour - associated tissue eosinophila , thereby prejudicing a comparison of the results .
for this reason alkhabuli and high   suggested the counting of eosinophils through a density method , which utilizes the highest density of eosinophils per surface area , in preference to the classic method that counts eosinophils / hpf .
in general , the presence as well as the state of activation of immunologic cells plays an important role in tumour cell progression .
further studies on eosinophils and their state of activation are necessary in order to elucidate these findings .
 the eosinophil cell has been related as a prognostic indicator for cancers . 
 however , its exact function in tumour behaviour is still not clearly defined . in the oral cavity 
 the presence of eosinophils can be a favourable prognostic indicator as well as it may be associated with a poor prognosis . in this short review , 
 we briefly summarize the role of the eosinophils in the general context of immunoregulation and its relation to oral squamous cell carcinoma . 
1. Introduction
2. The Eosinophil and Its Diverse Functions in the Context of Immunoregulation
3. Prognostic Value of Eosinophils in Oral Squamous Cell Carcinoma
4. Conclusion