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Mechanisms and applications of interleukins in cancer immunotherapy.

Anestakis D, Petanidis S, Kalyvas S, Nday CM, Tsave O, Kioseoglou E, Salifoglou A - Int J Mol Sci (2015)

Bottom Line: However, due to tumor heterogeneity and inter-tumoral discrepancy in tumor immunity, the clinical benefits are quite restricted.Emphasis will be given to new cytokines in pre-clinical development, and potential directions for future investigation using cytokines.To this end, the emerging in-depth knowledge supports further studies on optimal synergistic combinations and additional adjuvant therapies to realize the full potential of cytokines as immunotherapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of General Biology, Medical School, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece. anestaki@auth.gr.

ABSTRACT
Over the past years, advances in cancer immunotherapy have resulted in innovative and novel approaches in molecular cancer diagnostics and cancer therapeutic procedures. However, due to tumor heterogeneity and inter-tumoral discrepancy in tumor immunity, the clinical benefits are quite restricted. The goal of this review is to evaluate the major cytokines-interleukins involved in cancer immunotherapy and project their basic biochemical and clinical applications. Emphasis will be given to new cytokines in pre-clinical development, and potential directions for future investigation using cytokines. Furthermore, current interleukin-based approaches and clinical trial data from combination cancer immunotherapies will also be discussed. It appears that continuously increasing comprehension of cytokine-induced effects, cancer stemness, immunoediting, immune-surveillance as well as understanding of molecular interactions emerging in the tumor microenvironment and involving microRNAs, autophagy, epithelial-mesenchymal transition (EMT), inflammation, and DNA methylation processes may hold much promise in improving anti-tumor immunity. To this end, the emerging in-depth knowledge supports further studies on optimal synergistic combinations and additional adjuvant therapies to realize the full potential of cytokines as immunotherapeutic agents.

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The major immune system-related interwoven roles of cytokine interleukins in the various stages of carcinogenesis.
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ijms-16-01691-f003: The major immune system-related interwoven roles of cytokine interleukins in the various stages of carcinogenesis.

Mentions: Many members of the interleukin family participate in the involvement of immune system cells in tumor progression, by sculpting the immunogenic phenotype of tumors as they develop (Figure 3). Recognition that immunity plays a dual role in the tumor microenvironment (TME) interactions between tumors and the immune cells prompted a new dogma in cancer immunology, divided into three phases of cancer immunoediting: Elimination, equilibrium, and escape [69]. In the first phase, “elimination”, malignant cells are destroyed by immune system cells. The few tumor cells that manage to survive immune destruction then enter an “equilibrium” phase where molecular editing (mutations, gene rearrangement) takes place. During this stage, immune system cells and tumor cells live coexisting in the TME. The immune system, though not able to completely eliminate cancer, does not allow it to progress or metastasize further. In the third and final phase of this process, immunologically sculpted tumors begin to grow progressively and establish an immunosuppressive tumor microenvironment leading to uncontrolled carcinogenesis. In a recent study, innate immune cells exhibited cancer immunoediting activity in the absence of adaptive immunity. This activity required NK cells and IFN-γ, which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40+ agonists, thereby restoring editing activity in RAG2−/− × γc−/− mice. These results confirmed the fact that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting [70]. Furthermore, cytokine interleukin 17D (IL-17D) was highly expressed in certain unedited tumors but not in edited mouse tumor cell lines. Moreover, forced expression of IL-17D in edited tumor cells induced rejection by stimulating MCP-1 production from tumor endothelial cells, leading to the recruitment of NK cells. These cells then promoted M1 macrophage development and adaptive immune responses. IL-17D expression was also lowered in certain high-grade and metastatic human tumors, suggesting that it can be targeted for tumor immune therapy [71].


Mechanisms and applications of interleukins in cancer immunotherapy.

Anestakis D, Petanidis S, Kalyvas S, Nday CM, Tsave O, Kioseoglou E, Salifoglou A - Int J Mol Sci (2015)

The major immune system-related interwoven roles of cytokine interleukins in the various stages of carcinogenesis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307328&req=5

ijms-16-01691-f003: The major immune system-related interwoven roles of cytokine interleukins in the various stages of carcinogenesis.
Mentions: Many members of the interleukin family participate in the involvement of immune system cells in tumor progression, by sculpting the immunogenic phenotype of tumors as they develop (Figure 3). Recognition that immunity plays a dual role in the tumor microenvironment (TME) interactions between tumors and the immune cells prompted a new dogma in cancer immunology, divided into three phases of cancer immunoediting: Elimination, equilibrium, and escape [69]. In the first phase, “elimination”, malignant cells are destroyed by immune system cells. The few tumor cells that manage to survive immune destruction then enter an “equilibrium” phase where molecular editing (mutations, gene rearrangement) takes place. During this stage, immune system cells and tumor cells live coexisting in the TME. The immune system, though not able to completely eliminate cancer, does not allow it to progress or metastasize further. In the third and final phase of this process, immunologically sculpted tumors begin to grow progressively and establish an immunosuppressive tumor microenvironment leading to uncontrolled carcinogenesis. In a recent study, innate immune cells exhibited cancer immunoediting activity in the absence of adaptive immunity. This activity required NK cells and IFN-γ, which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40+ agonists, thereby restoring editing activity in RAG2−/− × γc−/− mice. These results confirmed the fact that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting [70]. Furthermore, cytokine interleukin 17D (IL-17D) was highly expressed in certain unedited tumors but not in edited mouse tumor cell lines. Moreover, forced expression of IL-17D in edited tumor cells induced rejection by stimulating MCP-1 production from tumor endothelial cells, leading to the recruitment of NK cells. These cells then promoted M1 macrophage development and adaptive immune responses. IL-17D expression was also lowered in certain high-grade and metastatic human tumors, suggesting that it can be targeted for tumor immune therapy [71].

Bottom Line: However, due to tumor heterogeneity and inter-tumoral discrepancy in tumor immunity, the clinical benefits are quite restricted.Emphasis will be given to new cytokines in pre-clinical development, and potential directions for future investigation using cytokines.To this end, the emerging in-depth knowledge supports further studies on optimal synergistic combinations and additional adjuvant therapies to realize the full potential of cytokines as immunotherapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of General Biology, Medical School, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece. anestaki@auth.gr.

ABSTRACT
Over the past years, advances in cancer immunotherapy have resulted in innovative and novel approaches in molecular cancer diagnostics and cancer therapeutic procedures. However, due to tumor heterogeneity and inter-tumoral discrepancy in tumor immunity, the clinical benefits are quite restricted. The goal of this review is to evaluate the major cytokines-interleukins involved in cancer immunotherapy and project their basic biochemical and clinical applications. Emphasis will be given to new cytokines in pre-clinical development, and potential directions for future investigation using cytokines. Furthermore, current interleukin-based approaches and clinical trial data from combination cancer immunotherapies will also be discussed. It appears that continuously increasing comprehension of cytokine-induced effects, cancer stemness, immunoediting, immune-surveillance as well as understanding of molecular interactions emerging in the tumor microenvironment and involving microRNAs, autophagy, epithelial-mesenchymal transition (EMT), inflammation, and DNA methylation processes may hold much promise in improving anti-tumor immunity. To this end, the emerging in-depth knowledge supports further studies on optimal synergistic combinations and additional adjuvant therapies to realize the full potential of cytokines as immunotherapeutic agents.

Show MeSH
Related in: MedlinePlus