Interferons – IFN) are signaling antiviral molecules. Dysregulation of the type I interferon system (IFN-I) can cause autoimmune diseases and inflammatory processes in non-autoimmune diseases, such as solid tumors and myocardial infarction.

Violations of the IFN-I system are observed in obesity. Obesity increases the risk of developing and progressing cancer. It increases susceptibility to infectious diseases and reduces the effectiveness of immune responses to vaccination. Obesity affects all stages of cancer development and may reduce the efficacy of antitumor therapy.

Type I interferons and cancer

IFN-I can exhibit antitumor activity through two main mechanisms:

1. Directly by affecting the tumor cells and affecting their properties and growth.

2. Indirectly-activating endothelial cells and cells of innate and acquired immunity: dendritic cells (DC), natural killer cells (NK), and T cells, contributing to the antitumor immune response.

Laboratory studies have shown that by binding to IFN-I receptors on tumor cells, IFN-I can suppress the expression of oncogenes, disrupting the reproduction of tumor cells and contributing to their death. Also, IFN-I can regulate the expression of tumor cell antigens, which are essential for both tumor growth and invasion and antitumor immunity. Numerous studies have shown that IFN-I reduces the risk of metastasis and inhibits the growth of cancer stem cells (CSC). However, other studies have shown that IFN-I may also contribute to tumor progression. At the same time, the successful response to traditional treatments, such as radiation therapy and chemotherapy, depends on the endogenous production of IFN-I. For more information, see the review covering the role of interferon in cancer.

How obesity and cancer are related

Being overweight and obese increases the risk of heart disease, hypertension, type 2 diabetes, non-alcoholic fatty liver disease, and cancer. Obese people have an increased risk of developing cancer with metastases and an increased likelihood of tumor recurrence. The survival rate in such patients is lower. Studies have shown a link between obesity and at least 13 different types of cancer.

Obesity is a chronic disease characterized by the accumulation of abnormal or excessive adipose tissue. Adipose tissue consists of adipocytes – fat cells and immune cells, stromal cells, blood vessels, and neurons.

The link between obesity and cancer risk was established almost 20 years ago. In obesity, cancer can be provoked by insulin resistance, increased regulation of sex hormones and the programmed cell death protein PD-1, and a violation of the release regulation of adipose tissue hormones – adipokines. Changes in the immune system caused by obesity can contribute to the occurrence and progression of cancer and affect the effectiveness of anti-cancer therapy.

The main sign of obesity is a chronic inflammation of moderate severity, local within the adipose tissue or systemic, affecting innate and acquired immune responses. Studies have shown that inflammation provokes cancer while reducing inflammation can prevent the development of cancer. Obesity-related changes in immune function increase the risk of infectious and chronic diseases, including cancer.

The immune dysfunctions observed in obesity depend on excess adipose tissue and adipocyte hypertrophy, promoting the release of pro-inflammatory cytokines both locally and systemically and on excessive levels of immune cells, especially macrophages. Obese individuals have reduced the anti-inflammatory adipokine adiponectin levels and increased levels of the pro-inflammatory adipokine leptin and other pro-inflammatory cytokines such as TNF-α, IL-6, CCL2, and IL-1β in adipose tissue.

Obesity affects the body’s immune defenses. Obesity alters lymphoid tissue, the development, differentiation, and function of immune cells, and the coordinated action of innate and acquired immunity. The integrity of the immune tissue structure is fundamental to the proper formation and maturation of white blood cells. In obesity, this structure changes due to fat deposits in the immune system tissues, including the bone marrow and thymus. That leads to a change in the distribution of white blood cells, lymphocytes’ activity, and a violation of the overall immune defense. In addition, obesity and insulin resistance are associated with a decrease in thymus function, a reduction in the size of the lymph nodes, and the number of T-lymphocytes. They also negatively affect the dynamics of secondary lymphoid tissues, reducing the repertoire of circulating T cells and thus limiting the range of responses to pathogens. Insulin resistance affects the processes involved in resolving inflammation, as insulin plays a significant role in triggering the differentiation of anti-inflammatory T helper cells 2 (Th2). At the same time, an overactive immune response due to excessive glucose uptake is associated with cancer and autoimmune diseases. In obesity, the function of NK cells involved in antitumor surveillance is disrupted, which increases the risk of cancer and cancer death in obese individuals.

Interferon type I and obesity

In obese patients, interferon production and signaling are impaired. It explains why obese patients are more susceptible to infectious diseases and to the progression of obesity itself.

Obesity-related immune dysfunctions increase susceptibility to viral, concomitant, and opportunistic infections involving multiple organisms, such as Mycobacterium tuberculosis, Coxsackie virus, Helicobacter pylori, influenza, and SARS-CoV-2 coronavirus.

During seasonal and epidemic influenza, people with obesity have higher morbidity and mortality. The antiviral response to the influenza virus in obese people is slowed and reduced. Therefore, they develop more severe lung inflammation, more damage from viral pneumonia, and these patients recover worse from the disease. Obese patients take longer to secrete the virus. In their body, a microenvironment is created, which contributes to the appearance of virulent mutations.

The effectiveness of antiviral drugs and vaccines is lower in obese people. It shows that obesity may play a role in changing the life cycle of the virus. Obesity reduces the already weakened immune response and leads to severe disease.

In the respiratory epithelial cells and macrophages of obese individuals, immune responses are disrupted, including IFN-I production and IFN-stimulated gene (ISG) signaling. At the same time, the production of inflammatory cytokines increases, and the number of pro-inflammatory M1 macrophages of the lungs increases. Thus, the lack of production and reduced transmission of IFN signals in obese patients may be one of the risk factors for severe outcomes of pandemic influenza infection.

During viral infections, the production of IFN-I and pro-inflammatory cytokines is reduced in obese people. That reduces the effectiveness of the body’s antiviral response. Reduced antiviral response in obese patients is associated with increased levels of the cytokine-3 signaling suppressor (SOCS3). SOCS3 is a crucial regulator of IFN-I and leptin and pro-inflammatory cytokines, which are elevated in obesity. Thus, increased SOCS3 regulation and altered systemic leptin levels may be responsible for decreased IFN-I response and other immune dysfunctions related to T and B cells in obese individuals.

Obesity increases the risk of viral infection. When the increased expression of SOCS3 was suppressed in peripheral blood cells from obese volunteers, the cells produced more IFN-alpha. In contrast, non-obese volunteers showed no increase in the IFN-alpha response, which confirms the key role of SOCS3 in suppressing IFN-I after stimulation of the TLR receptor responsible for the cellular immune response in obesity.

In addition to disrupting the IFN-I response in obesity, studies demonstrate a mutual regulation between IFN-I and metabolic processes.

IFN-I and the type I interferon receptor IFNAR are involved in the inflammation of adipose tissue observed in obesity, and the effects can be both harmful and positive.

Harmful effects of interferon in obesity:

• In obese people, visceral adipose tissue is a focus of low-grade chronic inflammation. In obese individuals, the fatty tissue hormone chemerin can attract plasmacytoid dendritic cells (pDC) from the bloodstream to visceral fat. Dendritic cells produce interferon, increasing inflammation and promoting systemic insulin resistance. Depletion of pDC and termination of IFN-I signaling prevents diet-induced obesity and type 2 diabetes.
• The expression of IFN-I in the liver, caused by obesity, promotes the accumulation and activation of intrahepatic CD8+ T cells, contributing to the metabolic syndrome.
• Interaction of the interferon type I receptor with IFN-I produced by primary adipocytes of a mouse or human origin increases the inflammatory activity of adipocytes.
• The deficiency of IRF7, the primary regulator of the IFN-I response, prevents high-fat diet-induced obesity (HFD) and insulin resistance. It indicates the involvement of IRF7 in diet-induced changes in energy metabolism and insulin sensitivity.
• Deficiency of the regulatory factor interferon IRF5 contributes to fat accumulation, insulin resistance, and increased levels of pro-inflammatory macrophages M1.
• Increased levels of IRF5 expression in adipose tissue are associated with overweight, obesity, and markers of inflammation.

Positive effects of interferon in obesity:

• Increased expression of IFN-β1, as well as administration of IFN-α-2b in mouse models of HFD-induced obesity, prevent weight gain and inhibit the infiltration of immune cells into adipose tissue, reduce adipose tissue inflammation and limit adipose tissue proliferation, or increase fatty acid oxidation and lower cholesterol, respectively.

• In a mouse model of diet-induced obesity, administration of IFN-tau, a member of the IFN-I family, increases insulin sensitivity, reduces the expression of pro-inflammatory cytokines, and increases the number of anti-inflammatory M2 macrophages.
• Antisense oligonucleotide T39 induces a non-targeted IFN-I response that protects against diet-induced obesity.
• Fat IFN-I signaling protects against metabolic dysfunction, obesity, and liver disease in mice fed a high-fat or methionine-choline-deficient diet.
• Weight loss and glycemic control caused by laparoscopic gastric banding in severely obese patients are associated with increased IFN-I response in the liver and adipose tissue.

Dual role of IFN-I in obesity

Obesity and colorectal cancer

Obesity is a risk factor for the vast majority of cancers. Among them, colorectal cancer (CRC) – tumor of the colon or rectum. CRC is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.

Among the causes of CRC are lifestyle, environmental factors, and genetic predisposition. The most potent influence on cancer is the combination of excess body weight with a violation of the diet. These factors are the most important in the prevention of colorectal cancer. Physical activity, maintaining healthy body weight, and eating a healthy diet can prevent CRC development.

Inflammation plays a vital role in the pathogenesis of CRC, and low-grade chronic inflammation, which characterizes obesity, is considered a significant risk factor for CRC. The observation further supports the link between inflammation and cancer that anti-inflammatory drugs reduce the risk of colorectal cancer and delay the development of intestinal tumors in patients with ulcerative colitis.

Diet plays a key role in the initiation and progression of colorectal cancer. By regulating several immune and inflammatory pathways, the diet can provoke inflammation locally in adipose tissue and systemically. In addition, the diet strongly affects the composition of the intestinal microbiota – microorganisms that inhabit the intestine. In obese individuals, the design of the microbiota is less diverse – dysbiosis is observed. At the same time, dysbiosis correlates with mild inflammation, an increase in body weight and fat mass, and type 2 diabetes. Commensal gut bacteria can directly contribute to carcinogenesis by supporting local mucosal inflammation or contributing to systemic metabolic and immune dysregulation and dysregulation of the antitumor response. In patients with CRC, changes in the microbiota of feces and mucous membranes are detected at different stages, characterized by a significant decrease in bacterial diversity. Combining these observations indicates that a healthy diet is an essential factor in maintaining the optimal composition of the intestinal microbiota, on which the body’s antitumor immunity depends.

IFN-I is produced in the normal intestinal mucosa, as well as in the tumor microenvironment. The microbiota regulates the IFN response. IFN-I supports the intestinal barrier functions, directs IgA antibodies against commensal bacteria, and controls the operation of intestinal macrophages. Through these mechanisms, IFN-I signaling supports intestinal immune homeostasis by enhancing innate responses to bacteria, enhancing intestinal barrier functions, and producing factors that prevent intestinal dysbiosis.

The expression and secretion of IFN-I in the tumor microenvironment play a vital role in the antitumor response. Measurement of IFN-I signals and signatures can serve as a predictive biomarker. The tumor suppresses the transmission of IFN-I signals in the tumor microenvironment, reduces immunity against CRC, and correlates with poor disease outcomes. IFN-I-stimulated genes (IRF1 and 2, IFITM1) expression is of prognostic significance and is associated with CRC risk, metastasis, and patient survival. IFN-I signaling in cancer and immune cells is a significant regulator of the antitumor response triggered by chemotherapy and radiation therapy. IFN-I inducers increase patients ‘ response to immune checkpoint inhibitors (CPIs), which block proteins that prevent T cells from killing cancer cells.

Conclusions

In obesity and cancer, type I interferons can play both beneficial and detrimental roles. The effect of IFN-I depends on its localization, the interferon subtype, and the intensity and duration of the IFN response.

Type I interferons in obesity:

+ IFN-I reduces obesity and metabolic disorders caused by a high-fat diet.

– An overactive IFN-I response in adipose tissue increases local adipose and systemic inflammation. This leads to a violation of the metabolism and the immune system, increases obesity, and provokes obesity-related diseases.

Type I interferons in cancer:

+ The presence of interferon-stimulated genes in the tumor microenvironment means a good prognosis during antitumor therapy.

– Prolonged transmission of the IFN-I signal can deplete T cells and lead to immunosuppression. It leads to the progression of the tumor.

The microbiota fine-tunes the IFN-I response. It regulates energy metabolism, the exchange of lipids and amino acids. Failure of regulation can lead to sustained IFN signaling, immunosuppression, and tissue damage, which is implicated in the pathogenesis of chronic viral infections, autoimmune diseases, and cancer.

The composition of the intestinal microbiota is influenced by diet. Improper eating behavior plays an essential role in the development of the tumor. A healthy diet is key to fine-tuning the interferon system and preventing obesity and cancer.

Source

Type I Interferons as Joint Regulators of Tumor Growth and Obesity

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