IL33 and Mast Cells—The Key Regulators of Immune Responses in Gastrointestinal Cancers?

Abstract

The Interleukin (IL-)1 family IL33 is best known for eliciting type 2 immune responses by stimulating mast cells (MCs), regulatory T-cells (Tregs), innate lymphoid cells (ILCs) and other immune cells. MCs and IL33 provide critical control of immunological and epithelial homeostasis in the gastrointestinal (GI) tract. Meanwhile, the role of MCs in solid malignancies appears tissue-specific with both pro and anti-tumorigenic activities. Likewise, IL33 signaling significantly shapes immune responses in the tumor microenvironment, but these effects remain often dichotomous when assessed in experimental models of cancer. Thus, the balance between tumor suppressing and tumor promoting activities of IL33 are highly context dependent, and most likely dictated by the mixture of cell types responding to IL33. Adding to this complexity is the promiscuous nature by which MCs respond to cytokines other than IL33 and release chemotactic factors that recruit immune cells into the tumor microenvironment. In this review, we integrate the outcomes of recent studies on the role of MCs and IL33 in cancer with our own observations in the GI tract. We propose a working model where the most abundant IL33 responsive immune cell type is likely to dictate an overall tumor-supporting or tumor suppressing outcome in vivo. We discuss how these opposing responses affect the therapeutic potential of targeting MC and IL33, and highlight the caveats and challenges facing our ability to effectively harness MCs and IL33 biology for anti-cancer immunotherapy.

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

“…Although it is unknown exactly how autoimmune tissue damage may trigger type 2 inflammation and tumorigenesis, IL33 could be a major player. IL33 is constitutively expressed in epithelial cells, endothelial cells, and fibroblasts and can be induced in hematopoietic cells like mast cells, macrophages, and neutrophils ( Afferni et al, 2018 ; Eissmann et al, 2020 ). Under physiologic conditions, IL33 localizes to the nucleus where it can regulate gene expression by binding to histones or influencing histone deacetylase activity ( Afferni et al, 2018 ; Larsen et al, 2018 ).…”

“…The ST2 receptor is expressed in most hematopoietic cells, particularly T reg cells, ILC2 cells, and mast cells ( Afferni et al, 2018 ; Figure 3 ). This pathway upregulates type 2 inflammation by skewing naïve CD4 + T cells toward Th2 or CD4 + T helper 9 cell differentiation, triggering ILC2 cells to secrete IL5 and IL13, activating mast cells, and driving M2 polarization of macrophages ( Afferni et al, 2018 ; Eissmann et al, 2020 ).…”

Multi-omics landscape and clinical significance of a SMAD4-driven immune signature: Implications for risk stratification and frontline therapies in pancreatic cancer

“…In addition, among the seven genes contained in SDIS, NDRG2 has been shown to be involved in tumor biological processes such as PI3K/Akt, apoptosis and autophagy [36] . IL33 also plays an integral role in tumor development and immune responses [37] . However, because these genes have shown great clinical predictive in tumors and few existing studies have been reported, the role and related mechanism of these genes in tumors need more studies in the future.…”

IL‐33/ST2 as a potential target for tumor immunotherapy

“…Recently, two papers demonstrated that IL-33 and ILC2s cooperate to suppress innate type 1 immunity and promote tumor development in lung cancer [20] and multiple myeloma [19]. Furthermore, current strategies used to target TME components also include inhibiting macrophage recruitment and differentiation and targeting CAFs and mast cells, also part of the IL-33-involved immune response [110,111].…”