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Prospects for cytokine and chemokine biotherapy
J J Oppenheim1, W J Murphy, O Chertox
1Laboratory of Molecular Immunoregulation, Divison of Basic Sciences, National Cancer Institute, Frederick, Maryland 21702-1201, USA.
Abstract:
Cytokines with immunostimulating effects have the capacity to induce tumor immunity in animal models, whereas some cytokines interfere with tumor growth based on their angiostatic effects. Despite these capabilities, cytokines, such as IFN-, IFN-, tumor necrosis factor, interleukin (IL)-1, and IL-2, have had limited clinical efficacy and many undesirable side effects. In preclinical models, cytokines can even promote tumor growth and increase metastatic spread. Although chemokines have had limited clinical evaluation, studies of animal models show that they can also have tumor-suppressive or tumor-enhancing effects. In mice, chemokines, such as IP-10, RANTES, and TCA3, have resulted in tumor regression and immunity to subsequent tumor challenge. Those chemokines that are angiostatic (e.g., PF4, IP-10, and MIG) can also induce tumor regression by reducing the tumor blood supply. Conversely, IL-8, which is angiogenic, can promote tumor growth. Our studies show that nasopharyngeal cell line cells (FADU) show a chemotactic as well as a proliferative response to MCP-1. In addition, a variant murine T cell lymphoma cell line Esb-MP, unlike the parental variant Esb, was selectively chemoattracted by murine MCP-1/JE. When injected s.c. into mice, the Esb-MP variant metastasized to the kidney with much higher frequency than the Esb variant. Both cultured kidneys from normal mice and a mesangial cell line constitutively produced chemoattractants that acted on Esb-MP but not Esb parental cells. Purification to homogeneity of these chemoattractants led to the identification of RANTES and JE. These results demonstrate that some chemokines may promote tumor growth and organ-specific metastatic spread of those tumors that have adapted and become responsive to chemokines. Finally, tumors appear to use numerous adaptive mechanisms to subvert and suppress the immune system. More effective therapy with cytokines and chemokines will require better characterization of the means by which tumors develop resistance to cytokines and overcome the immune system. Only then can we develop appropriate therapeutic approaches to antagonize cancer-induced immunosuppression.
Insights
Cytokines and chemokines show mixed effects on tumors, sometimes aiding growth and spread. Understanding how tumors evade immune suppression is key to developing effective cancer therapies.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Cytokines like interferons (IFN) and interleukins (IL) have shown potential in cancer immunity but have limited clinical success and side effects.
- Chemokines, though less studied clinically, exhibit both tumor-suppressive and tumor-enhancing effects in preclinical models.
- Some chemokines, like IP-10 and RANTES, promote tumor regression, while others, like IL-8, can enhance tumor growth.
Purpose of the Study:
- To investigate the dual role of chemokines in tumor growth and metastasis.
- To explore how tumors adapt to and utilize chemokines for their own benefit.
- To understand tumor mechanisms for immune evasion to improve cytokine and chemokine-based therapies.
Main Methods:
- Utilized mouse models with T cell lymphoma variants (Esb and Esb-MP) to study chemokine-mediated metastasis.
- Analyzed chemotactic and proliferative responses of nasopharyngeal (FADU) and T cell lymphoma cell lines to chemokines like MCP-1.
- Purified chemoattractants from mouse kidneys and mesangial cells to identify specific chemokines involved in metastasis.
Main Results:
- Nasopharyngeal cell line (FADU) and a T cell lymphoma variant (Esb-MP) showed chemotactic responses to MCP-1.
- The Esb-MP variant exhibited significantly higher kidney metastasis frequency compared to the Esb variant.
- Identified RANTES and JE as chemoattractants responsible for the enhanced metastasis of the Esb-MP variant.
Conclusions:
- Certain chemokines can promote tumor growth and organ-specific metastasis in adapted tumors.
- Tumors employ adaptive mechanisms to subvert the immune system and resist therapy.
- Further research into tumor resistance and immune suppression is crucial for developing effective cytokine and chemokine-based cancer treatments.