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1. Introduction
Cancer remains one of the main causes of mortality despite all efforts to decode the molecular mechanisms of the disease and to develop therapeutic strategies (1). Currently, there are three main approaches to treating cancer patients: Surgery, radiotherapy and chemotherapy. These three therapeutic approaches are named by the experts as ‘the pillars of cancer therapy’, but more and more oncologists are considering immunotherapy as ‘the fourth pillar’ (2). Immunotherapy either stimulates the activities of specific components of the immune system, or counteracts the signals produced by tumor cells which suppress the immune response. The concept of single therapy in cancer therapy has been discounted with each discovery related to the genetic and immunologic complexity of the tumor microenvironment (3-5). Currently, many studies have focused on increasing the effectiveness of antitumor therapy by combining established cancer treatment, such as chemotherapy, radiotherapy and photodynamic therapy with immunotherapy. Many efforts are also being made to identify new immune therapeutic targets and combinations of immunotherapeutic agents for increasing the response rates to therapies.
Immunotherapy began with the use of Coley's toxins in the treatment of osteosarcoma and has expanded to cytokines such as interleukin-2 (IL-2) and interferon-γ (IFNγ) to recently immune checkpoint inhibitors, anti-programmed cell death 1/programmed death ligand 1 (anti-PD-1/PD-L1) and cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) (6). Immunotherapy in cancer comprises immune system modulators (cytokines), therapeutic antibodies, immune cell therapy, immune checkpoint inhibitors, and vaccines (7).
In the last four decades, cytokines have been explored in large-scale clinical trials for patients with melanoma, renal cell cancer (RCC), breast cancer, glioblastoma, lymphoma, and leukemia (8). US Food and Drug Administration (FDA) has approved several cytokines and hematopoietic growth factors for adjuvant therapy in cancer. Interferon-alpha (IFN-α) and IL-2 are used in the treatment of RCC and metastatic melanoma, or as adjuvant therapy for patients with surgical excision of high-risk malignant melanoma (9). There are many studies that have reported a significant alteration of T and NK cell functions in cancer (10-12). The combination of IL-2 with adoptive T cell therapy has significantly improved treatment efficacy. These achievements indicate that stimulation of T and NK cell reactions may produce efficacious and lasting responses (13,14). Cytokines are immunomodulators; they act on both effector and cytotoxic cells. Various animal tumor models...