Immunomodulatory cytokines as therapeutic agents for melanoma

Abstract

Melanoma is the most aggressive form of skin cancer whose worldwide incidence is rising faster than any other cancer. Few treatment options are available to patients with metastatic disease, and standard chemotherapeutic agents are generally ineffective. Cytokines such as IFN-α or IL-2 can promote immune recognition of melanoma, occasionally inducing dramatic and durable clinical responses. Here, we discuss several immunomodulatory agents, the safety of which are being evaluated in clinical trials. Challenges include an incomplete understanding of signaling pathways, appropriate clinical dose and route, and systemic immunosuppression in advanced melanoma patients. We consider how targeted cytokine therapy will integrate into the clinical arena, as well as the low likelihood of success of single cytokine therapies. Evidence supports a synergy between cytokine immunotherapy and other therapeutic approaches in melanoma, and strengthening this area of research will improve our understanding of how to use cytokine therapy better.

Figure 1

Cytokine influence on immune, stromal and malignant cells present within the tumor microenvironment.

Figure 2. Representative signal transduction pathways of immunomodulatory cytokines

The numbers refer to the specific STAT and Jak molecules that are activated in that particular pathway. IL-2R: IL-2 receptor; STAT: Signal transducer and activator of transcription; Tyk2: Tyrosine kinase 2.

Figure 3. Effect of cytokines on immune cells in the tumor environment

While cytotoxic immune cells can be present in the tumor environment, tumor and surrounding stroma also have the capability of secreting immunomodulatory cytokines that can support immunosuppressive cells such as regulatory T lymphocytes and myeloid-derived suppressor cells. These cells inactivate NK and cytotoxic T cells, subsequently establishing a protumorigenic environment. ArgI: Arginase I; IDO: Indoleamine 2,3-dioxygenase.