Abstract 1355: Suppressors of cytokine signaling (SOCS) proteins are elevated in the melanoma microenvironment

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Immunosuppressive cytokines (IL-6, IL-10, TGF-β) act to promote tumor growth and suppress immune function. Conversely, the interferons (IFNs) are critical for cancer immunosurveillance by host immune cells. The precise mechanisms in which effector functions of immune cells are regulated by these cytokines deserve further investigation. Signal transduction in response to IFNs can be negatively regulated by the Suppressors of Cytokine Signaling or SOCS proteins. Our laboratory has demonstrated that SOCS1 and SOCS3 negatively regulate the anti-tumor activity of exogenously administered IFN-α by reducing intracellular signaling responses. In fact, SOCS1-deficient mice were cured of lethal melanoma tumors, and this effect was dependent on CD8+ T cells (Zimmerer et al., J. Immunol., 2007). Therefore, we hypothesized that cytokines present in the tumor microenvironment exert their immunosuppressive actions via the up-regulation of SOCS proteins in immune cells, making them less responsive to the cytokines that mediate immune surveillance. Treatment of peripheral blood mononuclear cells with IL-6, IL-10 or TGB-β led to increased expression of SOCS1 or SOCS3 proteins and pre-treatment with these cytokines inhibited subsequent IFN-α induced signal transduction and gene expression as measured by Real Time PCR. Since expression of IL-6, IL-10 and TGF-β has been observed at the tumor site, we postulated that increased expression of SOCS1 or SOCS3 proteins might also be present and serve as an initial barrier to the actions of IFNs on immune effector cells located in the tumor microenvironment. Lymphatic tissue from sentinel node biopsies represents a unique opportunity to study the interactions between melanoma cells and immune cells in the microenvironment. We therefore characterized the expression of SOCS proteins in formalin-fixed paraffin-embedded specimens from melanoma-positive or melanoma-negative lymph node (LN) biopsies. In melanoma negative LN, SOCS1 protein showed a characteristic histologic pattern of expression as it was strongly expressed in sinusoidal or perivascular lymphatic vessels, with a small number of scattered SOCS1 positive cells in the interfollicular zones. SOCS3 protein was primarily expressed within sinusoidal cells. Little or no SOCS1 or SOCS3 proteins were expressed in germinal centers. Evaluation of melanoma-positive LN revealed the presence of SOCS1 and SOCS3 positive cells that localized to the lymphoid or monocytic cells, rather than the tumor cells themselves. Of note, immune cells in close proximity to the tumor (200µM) displayed prominent SOCS1 and SOCS3 staining. These data indicate that the presence of melanoma tumors in lymphatic tissue is associated with elevated SOCS1 and SOCS3 protein expression in immune effector cells. Together these data suggest that SOCS proteins may play a role in the immune modulation within the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1355.