The biology of interleukin-2 efficacy in the treatment of patients with renal cell carcinoma

Renal cell carcinoma (RCC) is the eighth most common malignancy in adults in the United States. More than 50% of individuals present with metastatic disease and conventional chemotherapeutic strategies have been associated with poor response rates. Immunotherapy with Interleukin (IL)-2, however, induces durable remission, achieving > 10 year recurrence free survival in 5-10% of patients with advanced RCC. First described as a T cell growth factor, IL-2 has a wide spectrum of effects in the immune system. Some of the possible mechanisms by which IL-2 carries out its anticancer effects include the augmentation of cytotoxic immune cell functions and reversal of T cell anergy, enabling delivery of immune cells and possibly serum components into tumor. IL-2 indirectly limits tumor escape mechanisms such as defective tumor cell expression of Class I or Class II molecules or expansion of regulatory T cells. Indirect effects on the tumor microenvironment are also likely and associated with rather dramatic T cell infiltration during the global delayed type hypersensitivity response that is associated with systemic IL-2 administration. The IL-2 signaling pathway, its effects on immune cells, and its role in various independent mechanisms of tumor surveillance likely play a role but little substantive data defining a clear phenotype or genotype of IL-2 responders distinguishing them from nonresponders has emerged in the last 25 years since IL-2 therapy was initiated. At best, we can only speculate that the disturbed homeostatic host/tumor interaction is reset in a small subset of patients allowing an antitumor response to recover or ensue.