Advancing Cancer Immunotherapy through Mast Cell Reprogramming

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Advancing Cancer Immunotherapy through Mast Cell Reprogramming

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Advancing Cancer Immunotherapy through Mast Cell Reprogramming.

Mast cells (MC) are a type of myeloid cell found in the connective tissues of our bodies, containing granules filled with potent inflammatory mediators like histamine.

Historically, mast cells have been associated with the pathogenesis of allergies and autoimmune diseases.

However, it is now recognized that mast cells play a crucial role in determining the behavior of tumor cells and the tumor microenvironment.

They act as key orchestrators of anti-tumor immunity, regulators of the tumor stroma, and are linked to the intrinsic properties of cancer cells.

Nevertheless, their role remains controversial since MCs can exhibit pro-tumor or anti-tumor functions in different tumor types, depending on their location within or around the tumor and their interactions with other components of the tumor microenvironment.

Hence, mast cells represent an underappreciated yet promising target in cancer immunotherapy.

Biology of Mast Cells

MCs originate from hematopoietic stem cells in the bone marrow and circulate in the blood before migrating to peripheral tissues. They mature and differentiate into mature mast cells in response to tissue-specific chemotactic factors, cytokines (such as stem cell factor and IL-4), extracellular matrix proteins, and adhesion molecules. MCs are distributed in various body regions, including epithelial cells, mucous membranes, the gastrointestinal tract, mucus-producing glands, as well as in areas surrounding nerves and blood vessels.

Mast cells have various receptors on their surface, and when activated by their ligands, they can release a variety of factors. These factors include pre-formed molecules (histamine, tryptase, proteases, and proteoglycans) and newly synthesized lipid mediators (leukotrienes and prostaglandins), cytokines (IL-4, TNFα, TGF-β, IL-1β), and chemokines (IL-18, CCL2, CCL4). Pre-formed mediators are stored in large granules within MC cytoplasm. Each MC contains around 50-200 granules, and under appropriate stimulation, these granules are rapidly transported to the extracellular environment within seconds. This process is referred to as mast cell degranulation.

Mast cell degranulation occurs in two forms: allergic degranulation, where the entire granule contents are rapidly released into the extracellular environment, and piecemeal degranulation, where granule contents are released in a more controlled and specific manner. The most well-studied mechanism of mast cell degranulation is the cross-linking of antigen-specific IgE on high-affinity IgE receptor FcεRI, leading to rapid mast cell degranulation. Mast cells can also be activated by other mechanisms, such as damage-associated and pathogen-associated molecular patterns, toll-like receptors, complement proteins, and cytokines.

The consequences of mast cell activation, degranulation, and/or secretion of inflammatory mediators include the activation or attraction of other immune, stromal, neural, and epithelial cells, leading to changes in the local tissue microenvironment, such as vascular dilation, angiogenesis, and activation of systemic immune responses. Mast cell activation and/or degranulation can occur in a classical rapid manner, resulting in the massive release of inflammatory mediators and intense clinical manifestations like allergic reactions and vasogenic edema. However, with the gradual release of specific mediators, these processes can also occur gradually, leading to chronic inflammation and local tissue changes. The latter form of mast cell activation is particularly important in cancer.

Mast Cells in Cancer

Mast cells have garnered increasing attention in the context of cancer. However, their role is multifaceted and can either promote or inhibit tumor development under different circumstances.

Pro-tumor Functions of MCs

Mast cells can support angiogenesis, inflammation, and homeostasis, thereby promoting cancer development. They release proteases like tryptase and chymase, which can activate matrix metalloproteinases, leading to the degradation of the extracellular matrix and the surrounding tumor tissue, promoting tumor growth, angiogenesis, and metastasis. In addition, mast cells release VEGF, PDGF-β, and IL-6, promoting angiogenesis, cell proliferation, and tumor growth. In pancreatic cancer patients, the accumulation of mast cells within the tumor site is associated with poor prognosis. In a Myc-induced β-cell pancreatic cancer mouse model, inhibiting mast cell degranulation chemically reduced tumor development and angiogenesis.

Anti-tumor Functions of MCs

One of the crucial roles of mast cells in regulating tumor progression is their function as sentinel immune cells, releasing chemokines, cytokines, and other factors to recruit other immune cells to the tumor microenvironment and alter their functions. Mast cells release chemokines like CXCL10, CCL3, and CCL5, which recruit CD8+ T cells and CD4+ T cells to the tumor. These cells can further modulate T cell activity by secreting TNF-α. Histamine released by mast cells favors specific subsets of helper T cells or T regulatory responses, depending on the stimulated receptor. Activated mast cells have been shown to upregulate MHC-II and co-stimulatory molecules, serving as local antigen-presenting cells for T cells.

In summary, the net balance of pro-tumor and anti-tumor signals induced by mast cells in the tumor, stroma, and immune microenvironment determines how mast cells ultimately affect tumor growth. Properly understanding how these factors interact is of vital importance for researching mast cell biology related to cancer and identifying mast cells as an optimal therapeutic choice for improving cancer prognosis.

Interactions between MCs and other immune cells in the Tumor Microenvironment (TME)

Mast cells (MCs) also play a role in regulating the functions of other immune cells within the Tumor Microenvironment (TME), thereby influencing local immune suppression or anti-tumor immunity. For example, in a mouse model of liver cancer, activated MCs have been shown to promote the infiltration of myeloid-derived suppressor cells (MDSCs) and the production of IL-17 through the CCL2/CCR2 axis, recruiting regulatory T cells (Tregs) to the tumor site. Furthermore, MCs can enhance the inhibitory activity of MDSCs through direct interaction via the CD40L/CD40 axis. CD40L on MCs can also promote the expansion of regulatory B cells (Bregs) that produce IL-10.

On the other hand, in colorectal cancer, MCs can switch the function of Tregs, downregulating IL-10 and initiating the production of IL-17, acquiring a pro-inflammatory phenotype. It’s noteworthy that the skewing of MC-mediated Tregs and effector T cells toward Th17 depends on the crosstalk between the OX40L/OX40 axis and IL-6 production. Additionally, MC-derived TNF-α is crucial for T cell activation. MCs produce fibronectin and express co-stimulatory molecules, promoting the activation and proliferation of CD8+ T cells. MCs can influence the homing of effector CD8+ T cells to the inflammatory sites by releasing leukotriene B4. In a mouse melanoma model, it has also been observed that TLR2-activated MCs can recruit NK cells by secreting a high dose of CCL3. Besides CCL3, other factors secreted by MCs, such as IL-4, IL-12, and TNF-α, can activate NK cells.

The conflicting results mentioned above indicate that depending on the cancer stage, the location within or around the tumor, and the interaction with other cells in the TME, MCs and their mediators may have different roles.

Targeting Mast Cells in Cancer Immunotherapy

Due to MCs’ ability to exert either pro-tumor or anti-tumor activity depending on the tumor type, location, and signals received from the surrounding microenvironment, treatment strategies can be tailored to either eliminate or enhance MC function based on the context.

Targeting the c-Kit Signaling Pathway

Since c-Kit is crucial for the development, survival, and activation of MCs, tyrosine kinase inhibitors like imatinib, nilotinib, or dasatinib can effectively target MCs in conditions such as mastocytosis, arthritis, or allergic reactions. However, these drugs have limited applications in suppressing MCs’ tumor-promoting functions.

It’s important to note that imatinib, nilotinib, or dasatinib are not specific to c-Kit, as they also target other kinase receptors like PDGFR, Src, and Abl kinases, thus potentially causing off-target effects. To overcome these limitations, a monoclonal antibody targeting c-Kit, barzolvolimab, has been developed, but it has only been tested in c-Kit-positive gastrointestinal tumors so far.

Stabilizing MC Degranulation

Drugs that can inhibit MC degranulation, such as cromolyn or ketotifen, have been widely used to treat allergies. They have also been studied in various preclinical models of solid tumors. In a xenograft mouse model of thyroid cancer, cromolyn treatment significantly reduced the proliferation and growth of tumor cells.

Apart from stabilizing and preventing the release of mast cell mediators, targeting upstream signaling pathways of mast cells is another approach. Binding of IgE to FcεRI leads to receptor aggregation, followed by downstream phosphorylation of receptor tyrosine activation motifs, ultimately leading to the release of inflammatory mediators. From the perspective that mast cell-induced inflammation favors the induction of anti-tumor responses, anti-tumor IgE antibodies have been proposed. Especially in tumors with high mast cell infiltration, the high density of FcεRI and the longer half-life of antibodies make it an attractive therapeutic approach. In vitro studies have observed reduced degranulation of anti-tumor mast cells and decreased tumor cell growth with tumor-targeted humanized monoclonal anti-HER-2/neu IgE and humanized anti-CD20 IgE.

Targeting Other Activation/Inhibition Receptors

In addition to c-Kit and FcεRI, mast cells have various other receptors that can modulate their function in the TME; hence, these receptors could be potential targets for mast cell-specific anti-cancer therapies.

Stimulation of Toll-Like Receptors (TLRs) in MCs can lead to the specific secretion of cytokines, resulting in the recruitment and activation of immune cells, ultimately inhibiting tumor growth. In fact, the role of TLR agonists in cancer therapy is currently being evaluated. In a B16.F10 mouse melanoma model, the TLR2 agonist Pam3CSK4 induces MCs to release cytokines such as IL-6 and CCL3, mediating direct anti-proliferative effects on tumor cells and the recruitment of NK and T cells.

Other receptors have also been shown to be crucial for the interaction between MCs and immune-suppressive cells, such as CD40L and OX40L. MCs can also directly inhibit CD8+ T cell activation through the surface expression of PD-L1. Therefore, MCs may be another target for immune checkpoint blockade therapy in tumors. In a gastric cancer model, the inhibition of MC-related PD-L1 leads to increased T cell activation and the suppression of tumor growth.

Regulating MC Recruitment

One possible strategy for targeting MC therapy is to inhibit or enhance their recruitment by acting on chemotactic pathways. In addition to regulating MC maturation, proliferation, and degranulation, the SCF/c-Kit and FcεRI signaling pathways can also mediate MC migration. Therefore, inhibitors of c-Kit, BTK, Syk, and PI3K can also hinder MC trafficking within tumors.

Moreover, many different molecules produced by tumor cells or TME cells can induce MC chemotaxis, including CCL2, CCL5, CCL11, CCL15, CXCL12, VEGF, FGF2, fibronectin, and lipid mediators. Blocking these chemotactic inducers may represent a therapeutic strategy to impede the recruitment of MCs, thereby hampering their support for the tumor.

Targeted MC mediators

Direct modulation of mast cell mediators is an effective way to alter downstream mast cell activation, including targeting histamine or histamine receptors, proteases such as tryptase, and TNF-α.

Tryptase, a mast cell mediator released during mast cell activation, promotes angiogenesis and extracellular matrix degradation, leading to cancer growth, cell invasion, and metastasis. Tranilast, nafamostat mesylate, and gabexatemesylate are three mast cell tryptase inhibitors that have preclinically demonstrated anticancer activity in a variety of solid tumors as monotherapy or in combination with other cancer therapies, with most studies focusing on pancreatic cancer. , colorectal cancer and breast cancer.

TNF-α is another mast cell mediator that has long been implicated in the pathogenesis of inflammatory bowel disease, and TNF-α inhibitors ( such as infliximab ) are the mainstay of treatment. In a colitis study, infliximab treatment significantly reduced the incidence of colorectal cancer. The safety of a triple combination of ipilimumab, nivolumab and a TNF-alpha antibody ( infliximab or certolizumab ) is being studied in a Phase I clinical trial ( NCT03293784 ) in advanced melanoma .

Adoptive transfer of MC

People have also begun to study the adoptive transfer of MC in vivo and use the anti-tumor properties of MC for cell therapy to fight cancer. This approach should consider reprogramming MCs to release antitumor mediators only when in contact with tumor cells to avoid non-targeted molecule delivery, allergic reactions, or other side effects. Fereyoduni et al. made the first attempt in this regard, using HER2/neu -specific IgE- presensitized MC to effectively kill HER2/neu -expressing tumor cells in a breast cancer model in vitro and in vivo .

In summary, a series of preclinical studies on solid tumors strongly suggest that mast cells play a crucial role in anti-tumor immunity and cancer prognosis.

Mast cells may act as key orchestrators of anti-tumor immune responses but also present mechanisms of resistance to immune checkpoint blockade and other cancer therapies.

With the increasing application and research of mast cell-targeted therapies in allergic diseases, their potential in cancer immunotherapy is showing promising prospects.

Advancing Cancer Immunotherapy through Mast Cell Reprogramming

References:

1. Mast Cells: A New Frontier for Cancer Immunotherapy. Cells. 2021 Jun; 10(6): 1270.

2. Frenemies in the Microenvironment: Harnessing Mast Cells for Cancer Immunotherapy. Pharmaceutics. 2023 Jun 9; 15(6): 1692.

(source:internet, reference only)

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