Mutual Association between Autoimmune Diseases and Malignancies

In recent decades, due to variations in the lifestyle of human societies, the prevalence of autoimmune diseases and cancers have increased significantly. Imbalance in immune system responses is one of the key factors in this regard. There is a strong, dynamic, and mutual relationship between autoimmunity and cancer, although the underlying mechanisms of this relationship have not yet been elucidated. In some cases, therapeutic strategies used for the treatment of cancer and autoimmune diseases play a significant role in this relationship. Moreover, genetics, epigenetics, inflammatory and anti-inflammatory cytokines, lymphocyte plasticity, disease mechanism, and host symbiotic microbiota play an important role in this correlation.
A failure in tolerance, defects in apoptosis, the production of autoantibodies, autoreactive B and T lymphocytes, and ultimately the immune system's attack on self-tissues and cells can all lead to the development of autoimmune diseases. In addition, continuous exposure to inflammatory cytokines such as TNF-α and IL-1, external stimuli (such as low levels of lipopolysaccharide), and chronic infection leads to immune cell tolerance and dysfunction, which in turn results in autoimmune disease. In fact, autoimmunity is caused by an imbalance between regulatory T lymphocytes and helper T lymphocytes, an increase in the activity of the innate and adaptive immune systems, and the production of inflammatory cytokines. 
Recent studies indicate that systemic autoimmune diseases are associated with a higher occurrence of cancers and malignancies. Chronic and systemic inflammation of these autoimmunities is one of the key justifications for this hypothesis. Also, constant stimulation of the immune system makes it ineffective and anergic, which favors the development of cancer. These reports indicate that malignancies such as kidney cancer, lung cancer, thyroid cancer, melanoma, leukemia, hematologic malignancies, and lymphoma have a high incidence in patients with rheumatoid arthritis, as a systemic autoimmune disease. Surprisingly, some studies reported a reduced risk of cancers and malignancies such as colorectal, breast, cervical, and non-melanoma skin cancers in patients with rheumatoid arthritis. Patients with systemic lupus erythematosus, as a prototype of systemic autoimmune disease, have also been reported to be more susceptible to malignancies such as lymphoma, leukemia, central nervous system malignancy, kidney cancer, lung cancer, and hematologic malignancies. Interestingly, the risk of developing Prostate cancer, breast cancer, cervical cancer, and melanoma is reduced in these patients. Of course, it should be noted that in systemic autoimmunity, the increased risk of malignancy is more common. Also, it has been demonstrated that organ-specific autoimmune disorders are associated with a higher risk of cancers affecting that organ.
Today, cancer is a leading cause of death worldwide. Tumors can use the mechanisms of immune tolerance to overcome anti-tumor immune responses. In addition, tumors evade the antitumor immune response by downregulating the expression of tumor-associated antigens and major histocompatibility complex (MHC) molecules. Also, the tumor cells suppress antitumor responses by secreting soluble immunosuppressive factors such as interleukin-10 (IL-10), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), adenosine, and prostaglandins, or involving immune checkpoints such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain 3 (Tim-3), and lymphocyte activation gene 3 (LAG-3). In the tumor's microenvironment, immunosuppressive cells such as myeloid-derived suppressor cells (MDSC), regulatory T lymphocytes, tumor-associated macrophages (TAM), regulatory B lymphocytes, and regulatory dendritic cells may prevent antitumor responses.
As with autoimmunity, uncontrolled cytokine production or defects in cytokine signalling can contribute to cancer progression and recurrence. Today, chronic and uncontrolled inflammation is considered a carcinogenesis and progressive factor. With the development of cancers and malignancies, the immune system employs strategies similar to autoimmunity to limit the growth of cancerous tissue. As a result, in cancer therapy, attempts are made to induce similar strategies of autoimmunity against the tumor. Activating the immune system to fight cancer creates challenges that may predispose patients to autoimmunity.
Currently, research has revealed that various cancer treatment approaches, such as immune checkpoint inhibitors (ICIs), monoclonal antibodies, and adoptive immunotherapy, lead to immune-related adverse events (irAEs) such as autoimmune diseases. One of the main reasons for these adverse events is the induction of immune responses against tumor tissue following immunotherapy, which causes tissue damage, loss of self-tolerance, and autoimmunity induction. These adverse events can occur in the tumor target organ or in the other organs. PD-1 and CTLA-4 are two critical molecules that play a significant role in immune checkpoints, maintaining tolerance, and cancer therapy. In some patients, ICIs therapy causes immune-related adverse events such as chronic inflammation and autoimmune diseases which correlated with poor prognosis and reduced survival.
It seems that there is an important correlation between the processes associated with the development of autoimmunity and cancer. According to limited data in this field, it is essential to increase studies to identify biomarkers, polymorphisms, genetic and epigenetic predictors to assess this correlation and prevent the occurrence of autoimmune diseases and cancer simultaneously. In addition, immune-related adverse events can be predicted before drug administration to the patient by producing animal models and inducing both autoimmune disease and related malignancy.