CD200 is induced by ERK and is a potential therapeutic target in melanoma
Kimberly B. Petermann, … , Jonathan S. Serody, Norman E. Sharpless
Kimberly B. Petermann, … , Jonathan S. Serody, Norman E. Sharpless
Published November 15, 2007
Citation Information: J Clin Invest. 2007;117(12):3922-3929. https://doi.org/10.1172/JCI32163.
View: Text | PDF
Research Article Oncology

CD200 is induced by ERK and is a potential therapeutic target in melanoma

Abstract

Immune-mediated antitumor responses occur in patients with metastatic melanoma (MM), and therapies designed to augment such responses are clinically beneficial. Despite the immunogenicity of melanoma, immunomodulatory therapies fail in the majority of patients with MM. An inability of DCs to sufficiently activate effector cells may, in part, underlie this failure of the antitumor response seen in most patients. In this work, we show that mutation of N-RAS or B-RAF, signature genetic lesions present in most MMs, potently induced the expression of cell-surface CD200, a repressor of DC function. Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. CD200 mRNA expression correlated with progression and was higher in melanoma than in other solid tumors or acute leukemia. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect. These data indicate that in addition to its effects on growth, survival, and motility, ERK activation in MM attenuates a host antitumor immune response, implicating CD200 and its interaction with the CD200 receptor as a potential therapeutic target for MM.

Authors

Kimberly B. Petermann, Gabriela I. Rozenberg, Daniel Zedek, Pamela Groben, Karen McKinnon, Christin Buehler, William Y. Kim, Janiel M. Shields, Shannon Penland, James E. Bear, Nancy E. Thomas, Jonathan S. Serody, Norman E. Sharpless

×

Figure 4

CD200 is required for T cell repression.

Options: View larger image (or click on image) Download as PowerPoint
CD200 is required for T cell repression. (A) IL-2 production by T lympho...
(A) IL-2 production by T lymphocytes during MLRs with the addition of human melanoma cell lines with varying levels of CD200 expression. WM2664, SKMEL24, and SKMEL28 express high levels of CD200; PMWK, Mel505, and SKMEL187 express low levels of CD200. IL-2 production, as a marker of T cell activation, was determined by ELISA after 72 hours of incubation. Indicated statistical comparisons are between the indicated cell line versus T cells plus DCs only (**P < 0.005; ***P < 0.0001). Error bars are ± SEM. (B) MLRs in the presence of WM2664, SKMEL24, and SKMEL28 transduced with nonspecific hairpin (WMNS, SK24NS, SK28NS) and WM2664, SKMEL24, and SKMEL28 transduced with CD200 knockdown (WMKD, SK24KD, SK28KD). DCs and T cells were mixed with the indicated human melanoma cell lines with or without CD200 shRNA knockdown. IL-2 production was significantly higher in CD200-knockdown melanoma cell lines (WMKD, SK24KD, SK28KD) when compared with the parental melanoma cell lines transduced with a nonspecific shRNA (WMNS, SK24NS, and SK28NS). Error bars are ± SEM. (C) Quantification of T cell rosettes. WMKD and SK24KD show a significant increase in the formation of T cell rosettes when compared with their parental cell lines transduced with a nonspecific shRNA in MLRs. A mix of T cells and DCs was used as a positive control (far-left bar). Error bars are ± SEM. (D) WMKD and SK24KD show a significant increase in the formation of T cell rosettes when compared with their parental cell lines transduced with a nonspecific shRNA in MLRs. A mix of T cells and DCs was used as a positive control (far-left panel). Original magnification, ×100.