In addition, the expression of PD-L1 differs with the type of cancer, and has been reported to be highest among patients with NSCLC and lowest in melanoma, where PD-L1+ cells were mainly non-tumor cells that were present in the tumor microenvironment (51). therapeutics. expanded tumor infiltrating lymphocytes (TILs) with a high-dose IL-2 regimen and lymphodepletion for the treatment of patients with metastatic melanoma (17). In this IL-10 approach, TILs were rapidly expanded in the presence of anti-CD3, feeder cells and IL-2, and infused into the patients, and an overall response of 50% was reported in patients with metastatic melanoma (17). Drawbacks of IL2 therapy The effective use of IL-2 in cancer treatment is hampered by several drawbacks, the main one being its short serum half-life, which is mostly due to rapid metabolism and elimination by the kidneys (18). Thus, IL-2 has to be administered repeatedly (every 8 h) at high doses, which can lead to severe toxicity such as hypotension, cardiac problems and pulmonary edema (18). In addition, Krieg (18) have reported that the binding of IL-2 to high-affinity IL-2Ra-expressing endothelial cells causes acute vasodilation effects that, in turn, lead to the development of vascular leak syndrome. Cytokines in combination therapy Cytokines are a diverse group of molecules, each of which can be used to target specific cells and activate unique pathways to obtain an overall therapeutic effect. Cytokines can also be combined with other therapeutic agents that work synergistically in order to provide significant advantages over monotherapy (19). Ovarian cancer is a type of cancer in which combination immunotherapy has shown promising results; one of the emerging therapies for ovarian cancer is targeting its arginine auxotrophy by depriving it of arginine, using a recombinant human arginase, inducing autophagy and subsequenT cell death (19). On the other hand, combination immunotherapy has also been effective in the treatment of ovarian cancer. A study by Ingersoll has demonstrated that combining cellular therapy using peripheral blood mononuclear cells with IL-2 and IFN cytokines significantly increases the survival of an ovarian cancer xenograft mouse model (20). This is consistent with another study that has reported that such a combination also exhibited increased cytotoxic effects on two ovarian cancer cell lines compared with those of monotherapy (21). Additionally, combining interferon -2b and interleukin-2 cytokine treatment with adoptive cell transfer and cryosurgery has demonstrated promising results in patients with advanced oral mucosa melanoma (21). Other interleukins and cytokines in immunotherapy IL-2 has been extensively studied in renal cancer and melanoma; however, other interleukins are also emerging in the field of cancer immunotherapy (16). Interleukins such as IL-15, IL-10 and IL-21 are of major importance in cancer immunotherapeutic studies (7). IL-5 binds to the same receptor as IL-2 and activates STAT5 (7). However, IL-5 Anacetrapib (MK-0859) initiates a different downstream signaling pathway, which has different effects on CDC8+ cell differentiation and memory cell formation (3). IL-15 is crucial for the proliferation and maintenance of memory T cells as well as for promoting the survival and increasing the cytotoxicity of NK and CD8+ T cells (22). IL-15 also induces the Anacetrapib (MK-0859) release and proliferation of other proinflammatory cytokines such as IFN- (22). Notably, IL-15 has no affinity for Anacetrapib (MK-0859) the IL-2R chain (CD25) and thus does not activate Tregs (22). As a result, IL-15 has been extensively studied as an alternative of IL-2 in cancer immunotherapy. For example, in a recent clinical trial, patients with renal cell carcinoma, non-small cell lung cancer (NSCLC) and melanoma received subcutaneous IL-15 injections, and the results demonstrated a dose-dependent increase in the number of active NK cells (23). In addition, a number of patients exhibited marked disease stabilization, especially patients with renal cell carcinoma, who presented with 2 years of increased disease stability (23). However, one study reported that IL-15 has a very short serum half-life of only 2.5 h due to its small size, resulting in rapid elimination from circulation (24). In addition, high doses of IL-15 have deleterious effects on the lymphocytes (22). Thus, trans-presentation has been adopted as a solution for this issue by increasing the specificity of IL-15 and increasing its half-life (25). IL-15 binds to the high-affinity IL-15 receptor IL-15R on the cell surface, which stimulates IL-15 signaling in the neighboring cells (26). This process is of great importance in Anacetrapib (MK-0859) activating the cytotoxic immune response and has been studied as an approach to stimulate direct cytokine delivery to responsive cells (26)..