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

Abstract

Recent epidemiological studies have found an alarming trend of increased cancer incidence in adults younger than 50 years of age and projected a substantial rise in cancer incidence over the next 10 years in this age group. This trend was exemplified in the incidence of non-cardia gastric cancer and its disproportionate impact on non-Hispanic white females under the age of 50. The trend is concurrent with the increasing incidence of autoimmune diseases in industrialized countries, suggesting a causal link between the two. While autoimmunity has been suspected to be a risk factor for some cancers, the exact mechanisms underlying the connection between autoimmunity and cancer remain unclear and are often controversial. The link has been attributed to several mediators such as immune suppression, infection, diet, environment, or, perhaps most plausibly, chronic inflammation because of its well-recognized role in tumorigenesis. In that regard, autoimmune conditions are common causes of chronic inflammation and may trigger repetitive cycles of antigen-specific cell damage, tissue regeneration, and wound healing. Illustrating the connection between autoimmune diseases and cancer are patients who have an increased risk of cancer development associated with genetically predisposed insufficiency of cytotoxic T lymphocyte-associated protein 4 (CTLA4), a prototypical immune checkpoint against autoimmunity and one of the main targets of cancer immune therapy. The tumorigenic process triggered by CTLA4 insufficiency has been shown in a mouse model to be dependent on the type 2 cytokines interleukin-4 (IL4) and interleukin-13 (IL13). In this type 2 inflammatory milieu, crosstalk with type 2 immune cells may initiate epigenetic reprogramming of epithelial cells, leading to a metaplastic differentiation and eventually malignant transformation even in the absence of classical oncogenic mutations. Those findings complement a large body of evidence for type 1, type 3, or other inflammatory mediators in inflammatory tumorigenesis. This review addresses the potential of autoimmunity as a causal factor for tumorigenesis, the underlying inflammatory mechanisms that may vary depending on host-environment variations, and implications to cancer prevention and immunotherapy.

Keywords: autoimmunity; cancer; chronic inflammation; interleukin-13; interleukin-4; metaplasia; tumorigenesis; type 2 immunity.

FIGURE 1

Chronic type 2 immunity in autoimmune diseases may lead to transformation. Type 1 immunity is driven by its key cytokine IFNγ and type 2 immunity by the key type 2 cytokines IL4 and IL13. In several autoimmune disorders, type 1 immunity causes continuous or repetitive cycles of antigen-specific damage to tissues. Type 2 immunity counterbalances type 1 immunity and mediates wound repair. When “chronic would repair” ensues from chronic tissue damage, type 2 cytokines might induce cellular metaplasia and transformation which eventually leads to invasive malignancy.

FIGURE 2

CTLA4 insufficiency may lead to autoimmune tumorigenesis through type 2 inflammatory pathways. Professional antigen-presenting cells (APC) activate T cells by providing co-stimulation through antigen-loaded MHC and CD80/CD86. CTLA4 negatively regulates of T cell activity through at least three mechanisms. CTLA4 can bind to CD80/CD86 with high affinity and sequester CD80/CD86 from CD28-mediated co-stimulation. Alternatively, CTLA4 binding to CD80/CD86 may initiate intrinsic inhibitory signaling in T cells. Furthermore, CTLA4, especially with constitutive expression by regulatory T cells, binds to CD80/CD86 and removes them from the APC by transendocytosis. CTLA4 insufficiency impairs the regulation of T cells, leading to dysregulated type 1, type 2, and type 3 immunity. The proposed pathway for tumorigenesis focuses on dysregulated IL4/IL13-driven type 2 immunity. In secondary lymphoid organs, dysregulated Th2 cell-B cell interaction may lead to the development of lymphoma. In mucosal epithelia, type 1 and type 3 immunity may inflict epithelial damage while type 2 immunity initiates a Th2 cell-epithelial cell crosstalk that potentially leads to epithelial cell transformation.

FIGURE 3

Proposed mechanisms of cellular transformation by type 2 inflammation. Autoimmunity causes antigen-specific tissue damage and may lead to the release of IL33, which is constitutively expressed and acts as an alarm signal when released into the extracellular environment. IL33 binds to the ST2 receptor expressed on epithelial cells and induces Cancer Osaka Thyroid (COT), which in turn activates pathways that regulate cell proliferation (JNK, MEK/ERK). IL33 also binds to ST2 expressed on ILC2s, Th2 cells, or mast cells and activates them. These cells secrete the type 2 cytokines IL4 and IL13, which reinforce type 2 immunity and bind to IL4R/IL13R expressed by epithelial cells. Downstream activation of STAT6 upregulates Sonic hedgehog (SHH), a regulator of embryonic genes. IL4R/IL13R may also activate Notch2, which regulates cell fate and differentiation. IL4-, IL13-, and IL33-induced changes to gene expression are complemented by epigenetic changes. Type 2 signaling in epithelial cells downregulates a ten-eleven translocation enzyme (Tet), which converts methylated cytosine to 5-hydroxymethylcytosine (5hmC), a common cancer epigenetic marker. Altogether, type 2 signaling may induce transformation of epithelial cells. IL4R/IL13R-STAT6-GATA3 signaling also produces reactive oxygen species by upregulating NADPH oxidase homologs DUOX2 and NOX1, which generate reactive oxygen species. The type 2 immune cells also secrete granulocyte-monocyte colony-stimulating factor (GM-CSF), chemokines, and IL6 to recruit M2-polarized macrophages. These macrophages are well-known to mediate tumor progression, angiogenesis, invasion/metastasis, and resistance of cancer to treatment.