MCs have been documented to be involved in shaping the microenvironment in lymphomas, mostly by increasing the microvessel density, increasing angiogenesis and fibrosis thus leading to rogue advancement of lymphomas. Hodgkin’s lymphoma (HL), derived from mature B cells, is characterized by tumor cells, Hodgkin’s and Reed-Sternberg (HRS) cells in a smoldering inflammatory microenvironment (33). Abundance in tryptase positive MCs has been predominantly associated with inflammation and poor prognosis in patients with HL. Infiltration of TGF-β producing MCs in HL’s subtype-nodular sclerosis has been associated with the invasion of neoplastic cells, the development of fibrosis and progression of HL by the promotion of angiogenesis (10, 25). MCs were shown to promote HL cell growth in SCID mice in vivo (25). In HL, MCs have also been reported to interact directly with tumor cells via CD30-CD30L, causing HRS cells to become activated and proliferate could be important for HL pathogenesis (10–12). Indirect interactions between tumor cells and MCs caused by soluble factors produced by HRS cells, such as IL-9, IL-13, CCL5/RANTES are important for MC infiltration and proliferation (10, 11, 13, 26). MCs are, therefore, involved in shaping the HL microenvironment in terms of angiogenesis and fibrosis leading to advancement of tumor cells towards invasion and nodular progression.

Splenic marginal zone lymphoma (SMZL), is characterized by indolent neoplastic B cells that infiltrate the spleen and sometimes the BM (34). MCs are directly recruited by neoplasm cells in the tumor microenvironment and support the stromal cell proliferation, angiogenesis, extracellular matrix (ECM) remodeling in this B cell malignancy. Also, stromal cells highly express CD40 which recruits MCs expressing CD40 ligand, lead to the release of IL-6 with other pro-inflammatory cytokines, thereby activating B cells, increasing the survival and proliferation of neoplastic cells and contributing to pathobiology of SMZL progression (14).

B cell lymphoma (BCL) accounts for 90% of lymphoid neoplasms worldwide. The most common and aggressive form of non-Hodgkin lymphoma that occurs within the lymph nodes, but can be present anywhere in the body outside the lymphoid system, is diffuse large B cell lymphoma (DLBCL). Marinaccio et al. speculated that a decrease in MC density would result in reduced inflammatory signals and increased pro-angiogenic signals by regulatory T cells (T_regs) (17). Whereas, an increase in MC density can enhance inflammation and suppress the functions of T_regs thereby allowing the differentiation and expansion of T_h17 lymphocytes leading to angiogenesis (17). Feng et al. considered IL-9 to be a key driver of tumor growth by which T_regs recruited and activated MCs to mediate immune suppression in the tumor region (18). The interplay of infiltrating T_regs and MCs in the tumor microenvironment therefore promotes the formation of tumor vessels, maintains the growth and metastasis of tumor in BCL.

Primary cutaneous lymphoma (PCL) is a non-Hodgkin’s lymphoma also known as lympho-proliferative neoplasm of clonal B cell or T cell lymphoma largely associated with the skin (35). Studies have shown that there is an increased number of MCs present in both the cutaneous B cell lymphoma (CBCL) and cutaneous T cell lymphoma (CTCL) in peripheral rims of skin (15). In CTCL presence of MCs is correlated with reduced survival and increased malignancy in patients with progressive disease or advanced disease stage in Folliculotropic mycosis fungoides and Se´zary syndrome compared to stable patients or early disease stage in Mycosis fungoides (MF) (16). MCs are not only present in advanced stages of CTCL and CBCL, but have also extensively degranulated, which is much more noticeable in progressive form of these neoplasms, whereas more non-degranulated form of MCs are present in MF (15). In vitro study has shown that the supernatant of MCs obtained by treatment with calcium ionophore can induce the production of cytokines such as IL-17, IL-6 from tumor cells and increase the proliferation of primary CTCL cells (16). For the first time, Rabenhorst et al. have used a connective tissue-MCs depleted mouse model to demonstrate the delay in development of PCL thus highlighting the crucial role of MCs in controlling the tumor progression (16). Rabenhorst et al. also demonstrated that adding MC supernatant increased the proliferation of Sezary and CTCL cell lines whereas MC supernatant had no effect on the proliferation of SeAx and Mac2B CTCL cell lines when MC degranulation was inhibited by cromolyn (16). Therefore MCs play a pro-tumorigenic role in PCL, which is critical in the advanced stages of the disease and can be linked to disease severity.

T cell lymphomas (TCLs) account for the rare group of non-Hodgkin’s lymphoma group due to their low prevalence. Angioimmunoblastic TCL (AITL) is the uncommon aggressive subtype of the mature peripheral TCL that involves lymph node (36) and dysregulation of T cell immune response (37). The presence of micro-vessels with high endothelial venules is a prominent feature of AITL. There is strong correlation between MCs and number of blood vessels in TCL cases studied by Fukushima et al. Their study suggests that MCs are responsible for the angiogenesis and progression of AITL (19). Neoplastic follicular T_h cells in AITL have been shown to produce CXCL-13, which is responsible for the accumulation of MCs strongly expressing IL-6 in AITL speculated to foster a pro-inflammatory microenvironment and deregulated angiogenesis (20). In addition to studies documenting the pro-tumorigenic role of MCs in TCL, YAC-1 T cell lymphoma cells in direct contact with MCs or tumor cell supernatant when added to MCs was shown to induce degranulation of MCs (27). Interestingly, after co-treatment with histamine receptor antagonists and MC mediators, it was discovered that histamine receptors H2 and H4 are involved in inhibition of YAC-1 cell growth whereas histamine receptors H1, H2 and H4 are involved in enhancement of EL4 T cell lymphoma cell growth and overall regulation of β catenin pathway (27). Furthermore, Rabenhorst et al. demonstrated that MCs are crucial for the progression of EL4 TCL tumors in vivo using an inducible mast cell deficiency mouse model Mcpt5-Cre/iDTR and Kit mutant mice. Increased proliferation of EL4 cells and release of pro-inflammatory cytokines on in vitro treatment with MC or BMMC supernatant was also observed (16). MCs exhibited a pro-tumorigenic role on the EL4 TCL cell line, but they exhibited an anti-cancerous role on the YAC-1 TCL cell line, implying that MCs may exist as picket cells in the lymphoma microenvironment and play a critical role in the suppression or advancement of tumorigenesis, depending on tumor characteristics and histamine receptor profile present on neoplastic cells (27).

As discussed above there is a pro-inflammatory and pro-cancerous role of MCs in various lymphomas with an exception in a T cell lymphoma. It was also demonstrated that MCs showed no effect on the proliferation of L1210 cell line which is a murine lymphocytic leukemia cell line in vitro (27). Similar to lymphomas, tryptase positive MCs were found to be abundant in the BM of chronic myeloid leukemia (CML) patients and increased MCs number in different stages of CML conformed to increased microvessel density and the advancement of CML to AML, which is the blast phase or the advanced stage (21). Interestingly, MCs count in acute lymphoblastic leukemia transformation (ALLT) stage was comparable to that of the healthy control group, implying that MCs control angiogenesis in the early stages of tumor development, whereas tumor cells drive growth and angiogenesis in later stages, and growth becomes MC-independent (21).

Multiple myeloma (MM) is the malignancy of neoplastic plasma cells infiltrating the bone marrow. Similar to lymphomas and leukemias, patients with MM have an infiltration of tryptase positive MCs in their BM, associated with increased neovascularization and angiogenesis (22). Cytokines such as IL-6, VEGF, TNF-α, B cell activating factor, and receptor activator of NF-kB ligand are elevated in MM (28). IL-6 is required for the survival and proliferation of normal immature B cells in the BM, and it has been identified as the key growth and survival factor for myeloma cells (28). Raised IL-6 levels can be caused by both myeloma precursor cells and the presence of MCs (23, 29). Increased MC density has also been linked to increased angiogenesis factors found in BM of MM patients (24). Therefore, MC can either directly or indirectly contribute to the progression of MM.

c-KIT receptor is critical for the survival and development of MCs as MC depletion is shown in mouse models with c-KIT mutation (50). The targeting of c-KIT receptor is therefore one such strategy that may help to reduce the number of MCs in the tumor microenvironment of hematological malignancies. c-KIT is a tyrosine kinase receptor and can be targeted by numerous tyrosine kinase inhibitors used as anti-cancer drugs such as imatinib, sunitinib, sofrafenib, which bind and inhibit Bcr-abl fusion protein tyrosine kinase and are currently being used in CML (51), gastro-intestinal cancers and in thymic carcinoma (52). Other United States Food and Drug Administration (FDA) approved anti-cancer drugs that are studied to target c-kit include Amuvatinib, which has been clinically tested for lymphoma and small cell lung carcinomas, Axitinib, was clinically tested for advanced renal cell carcinoma, Cabozantinib, for prostate cancers and Dasatinib, for Chronic myeloid leukemia (52). A biologic inhibitor of c-KIT, KT0158, which is a humanized monoclonal antibody, has been shown to decrease MC degranulation and reduce MC numbers in a preclinical study (53).

In addition to c-KIT inhibitors, interestingly Fluvastatin, a statin drug used in the treatment of hypercholesterolemia not only suppresses IgE signaling in MCs but also induces apoptosis by inhibiting stem cell factor (SCF) induced survival signals in primary and in c-KIT mutated MCs (54). Consequently, the strategy to target the number of MCs would serve as an anti-inflammatory approach with a potential to suppress neo-vascularization, leading to a considerable delay in the tumor growth prior to the initiation of angiogenic switch. This strategy could prove to be a rational and effective additional therapeutic strategy for lymphoid neoplasms negatively affected by MCs.

MCs release pre-formed mediators present within their granules and newly formed lipid mediators instantly upon activation and other newly synthesized mediators are released 3-12 hours later. T cell lymphoma cells have been shown to activate MCs to a similar extent as an allergen and show similar release of pre-stored mediators (27). These mediators are further responsible for the inflammation and angiogenic progression in lymphoid neoplasms or the rejection of tumors as seen in some solid cancers like breast cancer. Therefore, if it is not possible to eliminate MCs, we can think about stabilization of MCs. MC Stabilization is a method of preventing the release of histamine and other mediators involved in rogue actions by impeding degranulation.

Bortezomib, an NF-Kβ inhibitor used to treat MM and other malignant hematological disorders, has been found to be minimally cytotoxic to MCs but can block MCs release, preventing fibrosis and vascularization in HL tumors in vivo. As a result, Bortezomib may be an interesting molecule to be used to kill malignant cells while simultaneously inactivating MCs in tumors, whereas Mizuno et al. claim that monotherapy may not work because the effect is transient (25).

Since histamine receptors are involved in responses to MC mediators, the use of MC antagonists may be helpful in reversing their response. Many MC stabilizers are now known to inhibit MC activation, such as H1 Histamine receptor antagonist Ketotifen, which is used to treat asthma and has been shown to suppress fibrosis (55). Azelastine, H1 receptor antagonist is a potent anti-inflammatory molecule that also inhibits release of histamine, tryptase and IL-6 from MCs (56). To inhibit histamine receptors in TCL cell lines, Pyrilamine as an antagonist for H1 Histamine receptor, Ranitidine as an antagonist for H2 histamine receptor, and JNJ7777120 as an antagonist for H4 receptor have been used (27). Some Tyrosine kinase inhibitors which are anti-cancerous agents such as Nilotinib, Sunitinib, Ibrutinib have been shown to have anti-histamine properties and can work as MC stabilizers (57–59). Not only chemical sources, but some natural sources of MC stabilizers such as flavonoids like luteolin, amentoflavone, bilobetin, quercetin (60, 61), phenols like curcumin (62) and alkaloids such as theanine present in green tea (63) have been shown to have antihistamine and MC stabilizing properties. It is therefore essential to identify and study how these stabilizers can be incorporated as add on therapeutic agents for the treatment of hematological malignancies.

As discussed in the section 1.1, MCs identified in haematological malignancies are tryptase-positive and are capable of causing neo-vascularization by secreting tryptase and chymase, which are potent angiogenic factors (64). Gabexate mesylate (GM), Nafamostat mesylate (NM) are tryptase inhibitors. NM is 100 times more potent than GM which is used in the treatment of acute pancreatitis and has been tested on several human cancer cell lines and Tranilast is used in the treatment of bronchial asthma and has a potential anti-tumor activity (65). Therefore, these molecules may be incorporated into treatments. As a result, targeting tryptase released by MC in the tumor microenvironment will serve as an anti-angiogenic strategy.

Although MCs have been shown to be involved in tumor progression, heparin, a MC mediator has been studied for its anti-cancerous role in many solid cancers (66). Heparin has been shown to attenuate metastasis in experimental cancer models possibly by inhibiting blood coagulation, inhibiting cancer cell–platelet and –endothelial interactions by selectin inhibition (67). It is therefore essential to study the role of heparin in hematological malignancies and thus strategies for including this molecule in cancer therapy.

Histamine is an important molecule that is pre-stored in MC granules and is the first molecule released when MCs are activated. Histamine has also been shown to be involved in cell proliferation, tumor development and embryonic development (68). The anti-cancerous properties of histamine in TCL have also been reported. Studies showed that histamine inhibits proliferation, decreases the survival and induces apoptosis in YAC-1 TCL cell line in vitro (27). Histamine dihydrochloride, a NOX2 inhibitor, targets MDSCs and improves immune-mediated clearance of neoplastic cells, thereby improving the immunotherapy efficacy of PD1 checkpoint blockade (69). Because of its receptor expression on immune cells as well as on tumor cells, histamine becomes an important molecule that can be strategically included in anti-cancer therapy and can have a detrimental effect on tumor depending on the construction of tumor microenvironment, cell types present and the histamine receptor expression profile.

Apart from the pro-tumorogenic role, MCs have been shown to have an anti-tumor role in some solid cancers such as melanoma, colon cancer, and colorectal cancer where MC presence in tumor is associated with improved patient survival (30–32), and also in a haematological neoplasm in vitro (27).

The tumor microenvironment contains sufficient chemokines and alternate molecules that can activate MCs. Chemotherapy and radiotherapy, as well as injury, cause dead and dying cells to release molecules known as alarmins or Danger-associated molecular patterns (DAMPs), which can activate MCs via TLRs and other receptors (70, 71). In hematological malignancies, alarmins such as IL-33 and Hsp-70 are commonly released, and cytokines such as IL-1 have been found to activate MCs and cause the release of IL-6 and TNF-α, while chymase from MCs has been shown to degrade IL-33 and Hsp-70 due to their ability to cause inflammation (70, 72, 73). Depending on the activation molecule and receptor activated on MC, the anti-tumor mechanism involves recruiting immune effector cells such as NK cells and cytotoxic lymphocytes, which can eventually lead to tumor cell clearance or the development of anti-tumor immunity. Virus activated MCs have been shown to degranulate and produce type I and type III interferons, CXCL8, CXCR1, and TNF, which can recruit and activate IFN-γ producing NK cells and NKT cells, allowing them to carry out cytotoxic actions which eliminate transformed cells (74–76). Interferon-stimulated chemokines have been found in tumors (32), therefore interferon-induced MC activation and NK cells recruitment may play a role in anti-tumor immunity.

Histamine, an important mediator released by MCs, is involved in the conservation of cytotoxicity receptors (NKp46, NKG2D) on NK cells in AML that are likely to be inhibited by phagocytes, and histamine prevents this inhibition by targeting H2 receptors on phagocytes (77). Histamine was used as a protector for cytotoxic lymphocytes and NK cells from phagocytes in a clinical study on AML where IL-2 was to be given as immunotherapy, which delayed relapse in patients and significantly improved the therapy (78). When activated, MCs also produce lipid mediators such as prostaglandins, leukotrienes, which are also involved in the recruitment of cytotoxic lymphocytes. As demonstrated in colorectal cancers that Leukotriene B4 derived from MC is in charge of recruiting and homing CD8+ T cells to the tumor site in order to generate anti-tumor immunity (79). As a result, MCs contribute chemokines, granule-associated and de novo synthesized mediators in tumor microenvironment, which may be important for immune regulation and anti-tumor responses.

To improve the recruitment of effector cells by MCs, innate immune activators such as TLR targeting immune-therapeutic molecules could be used. TLR-2 activated MCs have been shown to recruit NK cells and T cells in a melanoma model (30), whereas TLR-3 receptor activation on MCs increases T cell recruitment and regulates its functions (80). Therefore, TLR agonists can be combined with molecules that inhibit the release of pro-tumorigenic factors by MCs (as discussed in previous section), resulting in an effective anti-tumor response.