AllergoOncology: Role of immune cells and immune proteins

Abstract Background Immune cells and immune proteins play a pivotal role in host responses to pathogens, allergens and cancer. Understanding the crosstalk between allergic response and cancer, immune surveillance, immunomodulation, role of immunoglobulin E (IgE)‐mediated functions and help to develop novel therapeutic strategies. Allergy and oncology show two opposite scenarios: whereas immune tolerance is desired in allergy, it is detrimental in cancer. Aim The current review provides an update on the role of immune cells and immune proteins in allergy and cancer fields. Methods Authors investigated the role of relevant immunological markers and the correlation with cancer progression or cancer suppression. Results Activated immune cells such as macrophages ‘M1’, dendritic cells (DCs), innate lymphoid cells (ILC2), NK cells, Th1, follicular T helper cells (TFH), TCD8+, B lymphocytes and eosinophils have inhibitory effects on tumourigenesis, while tolerogenic cells such as macrophages ‘M2,’ tolerogenic DCs, ILC3, T and B regulatory lymphocytes appear to favour carcinogenesis. Mastocytes and alarmins can have both effects. RIgE antibodies and CCCL5 chemokine have an anticancer role, whereas IgG4, free light chains, Il‐10, TGF‐β, lipocalin‐2, CCL1 chemokine promote cancer progression. Fundamental is also the contribution of epigenetic changes regulated by the microRNA in cancer progression. Conclusion This knowledge represents the key to developing new anticancer therapies.

favouring cancer progression. Also, mast cells have a different effect on tumourigenesis based on multiple factors cancer-related. Eosinophils have shown a prevalent tumouricidal function mediated by α-defensins, TNF-α, granzymes A and IL-18. 1 IgE antibodies showed anticancer role while IgG4 induce immune tolerance and represent an escape to antitumor immune response. Free light chains (FLCs), regulatory cytokines such as IL-10, TGFβ, lipocalin-2 (LCN-2) and chemokines (e.g., CCCL1), promote cancer progression; however, CCCL5 chemokine has demonstrated an anticancer role. The group of alarmins (HGMB1, IL-1α, S100 proteins and IL-33) showed a different role, promoting or inhibiting tumour progression, depending on the type of the tumour, stage and their localization. 2,3 Finally, epigenetic changes regulated by microRNA (miRNA) exert a notable contribution to the immune response and cancer development. 4 The European Academy of Allergy and Clinical Immunology established a Task Force on AllergoOncology to evaluate the relationships between cancer and allergy with the goal of studying both allergic problems in clinical oncology and the immunomodulatory mechanisms eventually protecting cancer to develop new oncological immunotherapy (e.g., cellular vaccines expressing IgE-binding tumour antigens; recombinant antitumour IgE). 2,3 Studies in this field are constantly updated.

| Epidemiologic association between allergy and cancer
Several epidemiological studies have suggested inverse associations between allergic diseases and malignancies. Allergy published, in 2005, two well-documented studies on this topic. The first, carried out at the Stockholm Karolinska Institutet, 5 analysed the possible presence of neoplasia and the allergic condition of 70,000 patients, reaching a neutral conclusion that allergy does not protect or promote the onset of tumours. The second, realized at the University of Heidelberg in Germany, 6 was a review based on 80 previous epidemiological studies. In total, the clinical conditions of 52,000 patients were analysed, reaching a conclusion that allergy has a certain protective activity (actually, with some discrepancies) for tumours of colorectal cancer, breast, pancreas, brain (glioma, but not for meningioma) and leukaemia. On the contrary, allergy could be a risk factor for lung cancer. Other epidemiologic studies have explored the potential association between allergy history and cancer (first brain, lymphatic and haematopoietic cancers). However, most studies have relied on self-reported allergic history, being typically limited, retrospective and associated with potential biases. Successive observations have reported an inverse association between allergy and colorectal carcinoma, 7 but not with haematopoietic or prostate cancer. 8,9 One study reported an inverse trend between increasing blood eosinophil count and subsequent colorectal cancer risk. 10 Other studies also evaluated biological indicators of allergy history and immune function. The level of total and specific IgE seems to have an inverse relationship with the development of neoplasia such as melanoma, glioma, gynaecological tumours and female breast cancer. 11 A potential correlation between allergies and risk of haematologic malignancies (HMs) has been evaluated in numerous epidemiological analyses. The greater part of investigations has studied the relations between allergy and acute lymphoblastic leukaemia or lymphomas. 12 A report suggests a relatively augmented risk of HMs in women but not in men with a story of allergies to airborne allergens, particularly to grass, plants or trees, 13 while, in a population-based report from the Swedish cancer registries, an augmented possibility of lymphoplasmacytic lymphoma was stated in subjects who had history of any form of allergy founded on previous hospital discharge information. 14 Moreover, numerous findings indicate that asthma is a risk factor for acute leukaemia (AL) in children with Down syndrome, while skin allergies appeared to defend subjects from AL. 15,16 In a US veterans report, a history of total allergic situations as verified in the hospital records was correlated with a diagnosis of non-Hodgkin's lymphoma (NHL). Important correlations were also reported in patients with allergic situations such as dermatitis, alveolitis and erythema, but not asthma. 17 Different analyses suggest a positive correlation, especially for Hodgkin lymphoma (HL). 18,19 Finally, a possible correlation has been proposed between allergy and cutaneous lymphomas such as mycosis fungoides (MF). A story of allergic rhinitis was reported for 25.5% of patients with typical MF and 31% of subjects with atypical MF. However, the incidence of asthma and eczema was low. The total amount of IgE (IgE-t) and eosinophil counts were greater for subjects with typical MF than for controls and for subjects with atopic diathesis than for subjects without atopy. 20 Nevertheless, the findings were not always uniform. An inverse correlation was described primarily in case-control design analyses.
For instance, an inverse relationship with a story of allergies has been stated for HM, lymphomas, HL, NHL, acute lymphoblastic leukaemia and multiple myeloma. [21][22][23][24][25][26][27][28][29][30] The correlation between allergy and AL proposes that the two pathologies may have a shared biologic mechanism. Two hypotheses, such as 'missing immune deviation' and 'decreased immune suppression,' have been suggested to elucidate the biological basis of this assumption. Epidemiological analyses have demonstrated that changes of a microbial exposure are the main element motivating the rising frequency of atopic diseases (the socalled 'hygiene hypothesis'). 31 However, the immunological cause of this hypothesis is still debatable. The early explanations established that a deficiency of shifting of allergen-specific reactions from the Th2 to the Th1 phenotype (missing immune deviation) was responsible. This signifies that decreased stimulation of Toll-like receptors on natural killer (NK) cells and DCs induces a reduced generation of cytokines, such as IFN-α and IFN-γ, and IL-12 which not only stimulate the expansion of Th1 cells but also disturbed the growth of Th2 cells. Lately, however, the relevance of diminished action of T cells (reduced immune suppression) has been underlined. Agreeing to this theory, the reduced microbial burden does not operate by causing a diminished generation of Th1-polarizing cytokines, but by reducing the effects of Treg cells. 32 In both cases, there is a profound alteration in the functionality of the immune system. Moreover, to clarify the role of allergies as a risk factor for haematological diseases, it is possible considering the antigenic stimulation theory which suggests that chronic stimulation of the immune system will cause accidentally occurring pro-oncogenic mutations in proliferating cells. 33 In contrast, allergies as protective factors can be justified in terms of the immune-surveillance theory, which propose that allergic pathologies increase the immune system's capability to identify and eradicate neoplastic cells. However, more studies will be necessary to define which structure of the immune system of allergic patients may constitute a risk factor for haematological neoplasms.
At present, no conclusive results have been achieved and literature data are inconsistent and contradictory, suggesting the importance of immuno-epidemiology studies on cancer, that consider other interfering factors such as environment, lifestyle, age, sex, job, alcohol, smoking use, type and duration of allergic disease other than the simple allergic status.

| Macrophages
Macrophages are an essential component of innate immunity and play a leading role in inflammation and host defence. 34 They explicate their role through phagocytosis and generate reactive oxygen species (ROS), nitrogen intermediates and other cytotoxic factors. ROS and nitrogen intermediates are also responsible for the exacerbation of allergy and asthma severity. 35 They are professional antigenpresenting cells (APCs) involved in allergy and autoimmune response, especially in delayed-type hypersensitivity. Due to various signals, macrophages may undergo classical M1 activation (stimulated by TLR ligands such as LPS and IFN-ϒ) or alternative M2 activation (stimulated by IL-4/IL-13). The M1 phenotype expresses elevated levels of proinflammatory cytokines, reactive nitrogen and oxygen intermediates promote Th1 response and strong microbicidal and tumouricidal activity. In contrast, M2 macrophages are involved in parasite containment and promotion of tissue remodelling, tumour progression and to have immunoregulatory functions. 36 M1 was observed in exacerbation of lung injury and airway remodelling in allergic asthma via nitric oxide production. The presence of M1 macrophages in tumour microenvironment has been associated with extended survival of certain cancers 3 also through the production of several angiogenic and lymphangiogenic factors. 37 M2-polarized macrophages can be further divided into three subpopulations: M2a, M2b and M2c, according to specific stimulators (cytokines, chemokines). M2a is triggered by IL4 and IL-13 and positively correlate with the severity of airway inflammation in allergic asthma. 38 In cancer, a low M1/M2a ratio was associated with poor prognosis in a variety of murine and human malignancies. M2b and M2c are involved in immune regulation, tissue remodelling, angiogenesis and tumour progression. M2b is induced by IgG immunoglobulin complex and lipopolysaccharide (LPS) and are reported in the context of allergy as well as cancer. In allergy, IgG4 can redirect proallergic M2a macrophages to an M2b-like immunosuppressive phenotype. 39 This suggests a role of M2b in immune tolerance and so in allergen immunotherapy. On the contrary, in cancer, this phenotype seems to be correlated with disease progression. Recently, high serum level of IgG4 was found in colorectal cancer patients turning M2 macrophages to tolerogenic states favouring cancer environment. 40 M2c induced by glucocorticoids, TGF-β and IL-10 and support induction of Tregs, correlate with tumour progression and poor prognosis. 41 Tumour-associated macrophages (TAMs) differentiate from circulating monocytes, enrolled to tumour sites by pro-inflammatory chemokines (CCL2, CCL3, CCL5, VEGF, colony-stimulating factors GM-CSF and M-CSF). 42 The prevalence of macrophage phenotype in tumour environment depends on the type of tumour, stage and the place of the tumour. M1/M2 ratio determines the negative prognosis in glioma and breast cancer and the best prognosis in carcinoma of the stomach, colon, prostate and non-small cell lung. 43 Immune complexes with an antitumour IgE antibody or crosslinking of surface-bound IgE can polarize monocytes and macrophages to upregulate CD80 and the pro-inflammatory mediator TNFα. TNF-α can then stimulate the production of the macrophage chemoattractant protein 1 (MCP-1) by both monocytes and tumour cells, and trigger the recruitment of macrophages into tumour lesions and restriction of tumour growth. 44 In fact, it should be recalled that TNFalfa takes its name from the identification in tumour necrosis.
The M2 phenotype predominates in hypoxic areas and seems to have unfavourable effects in tumour growth.
New therapeutic strategies will be available to re-educate these macrophages promoting the positive effect of M1 phenotype. 45

| Dendritic cells
DCs are 'skilled' cells responsible of uptake, proteolytic processing and presentation of antigens to T cells. In an allergic condition, they activate naïve CD4+ T cells to differentiate into Type 2 helper T cell through the production of specific cytokines. Th2 cells and their cytokine production driven by IL-4 and IL-13 promote/facilitate the production of allergen-specific immunoglobulin E (IgE) from B cells.
Therefore, IgE-mediated antigen presentation supports DC-based immunity rather than leading to DC-mediated tolerance.  Although the effect of NK cells in subjects with allergy is inadequately analysed, some reports propose a responsibility for NK cells in allergic patients. Different experimentations confirmed that NK cells participate in Th1 cell expansion, allergen-specific immune suppression, as well as IgE generation. With respect to non-allergic subjects, augmented NK cell proliferation has been reported in subjects with allergic rhinitis. Moreover, the cytotoxic effect of NK cells in allergic subjects was also greater with respect to healthy controls, while the presence of NK cell costimulatory and inhibitory receptors in allergic subjects displayed heterogeneity in immune control. NK cells involve skin immune responses to hastens by producing type 1 cytokines. Finally, NK cells isolated from the skin of subjects with allergic contact dermatitis presented specific phenotypes. 47,48 Their cytotoxic role is important especially in the first phase of cancer immunoediting, known as 'elimination phase'. NK cells can kill tumour or virally infected cells without any necessity to be primed and proliferated by the first exposure. This is a promising feature for developing new treatments against cancer. Indeed, the prominent role of NK cells leads to future perspective in immunotherapy consisting in adoptive transfer of allogenic NK cells, use of NK cell lines, genetically modified NK cells and antibody therapies. 49

| Innate lymphoid cells
Innate lymphoid cells (ILCs) that include cytotoxic NK play a significant role in the early defence against infections, allergic inflammation, tissue repair and cancer editing. 50 They reflect helper T-cell subsets, but they do not express specific antigen receptors. ILCs are classified into three groups, based on their cytokine production.

| T and B lymphocytes
Th2 cells play an essential role in the induction and maintenance of the allergic inflammatory modulation by the production of IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13. They induce differentiation, activation and in situ survival of eosinophils (through IL-5), stimulate B-lymphocytes to produce IgE (through IL-4 or IL-13), and favour mast cell and basophil growth (through IL-4, IL-9 and IL-10). Their role in cancer is controversial. It has been observed that the shift in immune response from Th1 to Th2 is characteristic of patients with more aggressive tumours. 53 In some cancers, including breast, gastric and pancreas Data showed that the frequency of T FH cells in peripheral blood was significantly lower in NSCLC patients than in healthy controls. In both primary and metastatic tumours, infiltration of T FH cells was observed, suggesting that they participated in the antitumour immunity of NSCLC patients. Compared to other T-cell subsets, the T FH cells from the peripheral blood and the resected tumours of NSCLC patients presented elevated apoptosis and reduced proliferation capacity. The T FH cells from NSCLC patients were also less effective at downregulating IgD and upregulating CD27 expression in naive B cells, and induced less IgM, IgG and IgA secretion, than those from healthy controls. Overall, it can be concluded that T FH cells were involved in the antitumour immunity and were associated with better clinical outcomes but suffered strong immunosuppression in NSCLC.
Enhancing the T FH cell activity, therefore, represents a potential therapeutic strategy in NSCLC. 68   to block inflammatory and neoplastic angiogenesis. 71,72 In the tumour microenvironment (TME), multiple stimuli activate mast cells including anti-tumour antibodies, hypoxia, alarmins, cytokines and chemokines. 73 Stem cell factor (SCF) seems to be one of the most important substances attracting mast cells into TME where they secrete pro-angiogenic factors, which promote tumour vascularization and invasiveness. Products attracting mast cells in TME includes angiopoietins and several chemokines (CXCL8, CXCL2, CXCL1, and CXCL10, PGE 2 , TSLP and osteopontin). Furthermore, SCF stimulates mast cells to produce matrix metalloprotease-9 (MMP-9) that facilitates the recruitment of other mast cells to the tumour and increases tumour-derived SCF production in an amplification feedback loop.

| Mucosal-associated invariant T cells
Mast cells may also suppress the development of protective antitumour immune responses by promoting regulatory T-cell-mediated suppression in the tumour microenvironment. [1][2][3] Thus, mast cells can have both tumour-promoting and tumourinhibiting immunoregulatory effects. It seems that their role depends on microlocalization, stage of tumour and on mast cells density in intratumourally and/or peritumourally. [1][2][3] In TME it is possible to distinguish anti-tumourigenic mast cells In certain neoplasia (e.g., thyroid, gastric, bladder, pancreas, Hodgkin's and non-Hodgkin's lymphoma) mast cells play a protumourigenic role, in others (e.g., breast cancer) a protective role, whereas in yet others they are apparently innocent bystanders. In stage I NSCLC, but not in stage II, peritumoural, but not intratumoural mast cell density is an independent favourable prognostic factor; mast cells were pro-tumourigenic in the initial stages of prostate cancer but not in the later stages; in perilesional stroma of melanoma play a protective role. In pancreatic ductal adenocarcinoma, mast cell density in the intratumoural border zone, but not the peritumoural or the intratumoural centre zone, was associated with a worse prognosis. In prostate cancer, high intratumoural mast cell density was initially associated with good prognosis. Generally, it was reported that intratumoural mast cells inhibited tumour growth, whereas peritumoural mast cells stimulated human prostate cancer. 75 These findings suggest that the microlocalization of mast cells should be investigated in various stages of clinical and experimental tumours. Last but not the least, the protumourigenic activities of mast cells can be subverted by targeting cells to promote tumour destruction. Furthermore, mast cells cause tumour cells death, in an in vitro lymphoma model, when incubated with an anti-CD20 IgE antibody. 76 These findings represent the potential to deviate the response of these cells against cancer through immunotherapies.

| Epithelial cells
Epithelial barrier has an essential role to balance immune response.
Epithelial cells surface includes the high and low-affinity IgE Fc receptors facilitating antigen passage and direct antigen presentation.
Epithelium constitutes a source of cytokine and contributes to modulation of the immune response both in allergy and in cancer.

Intestinal epithelial cells of extracellular vesicles contribute to innate
immunosuppression that generate oral tolerance or cancer progression. 3,82 Role of different immune cells in cancer is listed in Table 1.

| IgE
IgE is an evolutionarily conserved member of the Ig family with the highest determined affinity to receptors and antigens among all antibody classes. 83  Several epidemiological studies reported an inverse association between atopy and cancer (pancreatic, prostatic, colorectal cancer, brain tumour, melanoma, breast and gynaecological cancers, chronic lymphocytic leukaemia, and multiple myeloma). However, one study of postmenopausal women showed no association between selfreported environmental allergies and incident myeloid or lymphoid malignancies. 86,87 These findings suggest that the relationship between atopy and malignancy is complex and probably depends on tumour types and the individual studied populations. Despite some mixed results, a 2016 review tabulating the body of epidemiological evidence of the relationship between atopy and cancer risk since 1995, suggested that atopy was associated with a reduced cancer risk. 88 Interestingly, IgE deficiency (IgE <2.5 kU/L or IgE <2 kU/L) is associated with a higher risk of malignancies 89 and ultra-low IgE is a potential novel biomarker in cancer. DI GIOACCHINO ET AL.

| IgG4
Allergen immunotherapy aims to achieve immune tolerance to a specific allergen. IgG4 is a marker of immune tolerance supported by IL-10 and TGF-β cells, such as T and B regulatory cells. While immune tolerance is a goal in allergy field, in tumour microenvironment represents an antitumour immunity escape. IgG4 might repolarize M2a macrophages to the immunosuppressive phenotype M2b, which could be responsible for increased IL-10 secretion. IgG4 is expressed in tissues from patients with malignancies such as melanoma, in whom it can impair antitumour immunity and correlates with shorter survival and disease progression. 90 There is also increasing evidence to support positive correlations between IgG4-related diseases, such as sclerosing cholangitis associated with autoimmune pancreatitis, with enhanced cancer risk. Elevated IgG4 has been detected in extrahepatic cholangiocarcinoma, colorectal cancer, pancreatic cancer, melanoma and glioblastoma. 91

| Free light chains
FLCs are a product of immunoglobulin heavy chains. FLC levels have been measured in allergic diseases (asthma, rhinitis), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, diabetes, inflammatory bowel disease and cancer. 92 In allergy fields, immunoglobulin FLCs induced non-IgE-mediated mast cell activation and release of mediators without degranulation. 93 In the latter, FLC seems to contribute to cancer progression through antigen-specific mast cell activation and reduce neutrophil apoptosis and stimulate the release of pro-tumourigenic IL-8. FLC was found to be a biomarker for poor prognosis in basal-like breast cancer; it was demonstrated that FLC stimulated tumourigenesis through mast cell activation in melanoma model. 94

| Regulatory cytokines (IL-10, TGF-β) and chemokines (CCCL1, CCCL5)
IL-10 and TGF-β are regulatory cytokines with a pivotal role in immune tolerance in allergy field whereas promoting cancer growth and progression. CCCL1 is a chemokine expressed by monocytes and by tolerogenic M2b macrophages subtypes and have a regulatory role.

Cells
Tumour-promoting effect

| Lipocalins
Lipocalins are innate defence proteins. Lipocalin-2 (LCN2) is upregulated in various cancer types, while they are decreased in allergic and atopic state and this, also has been proposed as a cancer biomarker. 3,95 3.6 | Alarmins (HMGB1, IL1-α, S100 and IL-33) Alarmins are proteins released from host cells after activation or when cells are damaged or died. 96  This mechanism was recently shown to be mediated by the activation of the JAK/STAT1 (Janus kinase/signal transducer and activator of transcription) pathway. 100 The redox state of HMGB1 too is believed to orchestrate its extracellular function. 101 Extracellular HMGB1 mediates inflammation, cell migration, proliferation and differentiation. 102,103 Cytoplasmic HMGB1 is involved in immune responses by increasing autophagy, inhibiting apoptosis and regulating mitochondrial function 104 (Figure 2).
In the extracellular space, HMGB1 binds to receptors like receptor for advanced glycation end products (RAGE), TLR4, TLR2, IL-1R, CXCR4, IL-1β and CXCL12. In DCs, HMGB1 release and sensing by RAGE was shown to be critical for homing to the lymph nodes and further cross-activation of T lymphocytes. [105][106][107] In endothelial cells, HMGB1 was shown to promote the expression of RAGE and surface adhesion proteins (intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) and to induce RAGE-dependent cytokine production. 108 Interestingly, yet another receptor of HMGB1, TIM-3, expressed at the surface of tumour-associated DCs, was recently shown to compete with nucleic acids for binding to HMGB1, thereby dampening the efficacy of antitumour DNA vaccines or chemotherapy. 109 Moreover, during apoptotic cell death, ROS production induces the terminal oxidation of HMGB1 that inhibits its proinflammatory function and switches HMGB1 function toward tolerogenicity. Therefore, HMGB1 might be a potential target for the treatment of inflammation.
In allergy field, HMGB1 could aggravate eosinophilic inflammation in the airway of acute allergic asthma through inducing a dominance of Th2-type response and promoting the neutrophilic inflammation. 110 For several years, HMBG1 was studied for his role in cancer development and nowadays it is considered one of the most modulators of cancer microenvironment. 111 On the one hand, HMGB1 can contribute to tumourigenesis. On the other hand, HMGB1 plays a protective role in the suppression of tumour and tumour chemoradiotherapy and immunotherapy. HMGB1 expression increases in many types of cancer, correlates with tumour invasion and metastasis, and relates to worse prognosis. 112 Combining role with RAGE, contribute to chronic inflammation and tumourigenesis. Further emphasizing the role of the RAGE-HMGB1 axis in cancer progression, blockade of either HMGB1 or RAGE can reduce malignant mesothelioma and glioma tumour growth and metastasis. 113 In contrast, oxidized HMGB1 promoted cell death and increased the efficiency of chemotherapeutic drugs. In addition, HMGB1 has been implicated in the antitumour immune response induced by radiation therapy or chemotherapy. 114 In any case, further studies are needed to ulteriorly clarify the role of this alarmin.

| IL-1α
IL-1α is a dual function cytokine with both nuclear and extracellular functions. As HMGB1, it is involved in inflammation and cancer. 115 IL-1α precursor is expressed in the nucleus of non-hematopoietic cells (epithelial cells of gastrointestinal tract, kidney, liver and skin), as a transcription factor, regulate gene expression and growth and differentiation of cells. 116 In stimulated cells, IL-1α is processed by the membrane-bound protease calpain, a calcium-dependent cysteine protease, and then released into the extracellular space. Furthermore, to calpain-and caspase-1-dependent pIL-1α processing, other proteases, such as granzyme B, elastase or chymase cleave pIL-1α, producing the mature form of IL-1α and potentiating its proinflammatory activity. 117  In allergy field, IL-1alpha administration during sensitization of Th2-mediated allergic reactions has been shown to suppress the course of disease by shifting the immune response towards Th1. 121 3.6.3 | S100 S100 is part of the S100 family of proteins composed of 25 members with different intracellular and/or extracellular functions. They have a high grade of similarity in sequence and structure, but they are not interchangeable, and they have different biological functions. S100 proteins are crucial proteins for calcium homeostasis and the main- S100A8/A9, S100A12 and S100 B are even considered biomarkers of specific diseases, such as cancer, atherosclerosis and stroke. 126 S100 proteins lack a signal peptide for secretion via the conventional Golgi mediated pathway, and their secretion can occur passively upon cell necrosis or actively after cell activation. S100A8/ A9 are extremely sensitive to oxidation and their redox state acts as a molecular switch from a proinflammatory function (reduced) to a protective wound-healing and antioxidant function (oxidised). 127 In contrast, oxidation of S100B was shown to be necessary for binding to RAGE and the subsequent increase in the expression of the angiogenic factor VEGF, an important player in the development of macular degeneration. 128 Innate cytokines such as IL-1, IL-33 and thymic stromal lymphopoietin (TSLP), as well as the alarmins HMGB1 and S100 proteins programme DCs to mount Th2-cell-mediated immunity and stimulate ILC2, basophil and mast cell function. 129 Like other alarmins mentioned above, S100 proteins have a significant role in cancer development promoting cell proliferation, metastasis, angiogenesis and immune evasion. However, they have different profile roles depending on type and stage of tumour. [130][131][132] The dysregulation of S100 protein expression is a common occurrence in many human cancers. Inhibitors directly targeting two family members, S100 B and S100A9, are in clinical trials for melanoma and prostate cancer, respectively. S100 proteins expression are also linked with drug resistance and are involved in chemotherapy response. Every cancer has a specific S100 expression profile. S100 proteins are widely studied in breast cancer, lung cancer, melanoma, ovarian cancer, colorectal and pancreatic cancer, and they represent a source for therapeutic opportunities. 133 Potential S100 inhibitors are classified in small molecules inhibitors, neutralizing antibodies and miRNA mimics. Small molecules inhibitors inhibit transcription of S100A4, S100A9, S100A10, S100B and S100P. Also, several studies with antibodies neutralizing S100A4, S100A7, S100A8/S100A9 and S100P are in preclinical phase. Several miRNAs were introduced to target the expression of S100 proteins. For instance, miR-187-3p and miR-149-3p were found to downregulate S100A4 expression. 134 Role of different S100 proteins is listed in Table 2. 3.6.4 | IL-33 IL-33 is IL-1 family member of cytokines exerting pleiotropic functions. 135  majority of ligands as AGEs, several S100 proteins (S100A4, S100A6, S100A7, S100A8, S100A9, S100A8/9, S100A12, S100B and S100P),
Interestingly, type 2 cytokines promote tumour metastasis and contribute to chemoresistance, and miR-126 has been shown to promote tumour angiogenesis via a TH2-dependent IL-13 release mechanism, in a model of breast tumour metastasis. 174 Furthermore, high miR-126 expression in acute myeloid leukaemia patients has been associated with a higher incidence of relapse and, additionally, poor survival. 175 Circulating miRNAs have been examined in numerous cancers, type II diabetes, neurodegenerative diseases, lung diseases, such as asthma and cardiovascular diseases. [167][168][169][170][171][172][173][174][175] The relation between miRNA and cancer are shown in Table 5 and summarized in Figure 3.
Several studies have suggested a crosstalk between immune cells and cancer via miRNAs. As changes to miRNA expression are seen in numerous diseases from cancers to respiratory diseases, it is becoming more apparent that they might be used as viable biomarkers for new therapeutic treatments. Mimics of let-7 and miR-34 have been tried in murine models of lung cancer, leading to reduction in the volume of the tumours. 176

| CONCLUSIONS AND FUTURE PERSPECTIVES
The ''immunebalance'' is a delicate mechanism that immune system uses to maintain homeostasis. Immune tolerance in allergy and cancer could represent a valid key to develop new anti-cancer therapies.
While allergen immunotherapy (AIT) may re-establish tolerance involving Tregs, IL-10 and TGFβ, and class switching to anti- Another recent anti-cancer therapy is provided by CAR-T-cell therapy which consists in the use of T cells engineered to express chimeric antigen receptors (CARs) with tumour specificity.
-13 of 19 The strong antitumour effect of IgE antibodies consented to generate engineering antibodies, and a recombinant anti-cancer IgE has shown encouraging results in the clinical setting. [84][85][86] Other interesting anti-cancer strategies to be developed