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, genomewide 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. IntroductionMelanoma, the most lethal form of skin cancer, has increased in incidence and mortality over the last 3 decades. Metastatic disease that is not amenable to surgery is generally refractory to therapy and, therefore, ultimately lethal. Standard chemotherapy typically produces response rates on the order of 10%, and radiotherapy plays only a limited role in disease palliation. Despite these sobering facts, some optimism has been engendered by recent advances in our molecular understanding of the disease, particularly the finding that approximately 80% of metastatic melanomas (MMs) harbor mutually exclusive activating mutations of either N-RAS or B-RAF (reviewed in ref. 1). These lesions lead to activation of the RAF/MEK/ERK/MAPK pathway, which in turn controls the transcription of hundreds if not thousands of genes related to cellular proliferation, survival, and motility (2). Although work in murine models and pharmacological approaches have suggested that RAS-RAF activation is required not only for tumor formation, but also for tumor maintenance (3, 4), the cell-biological effects of ERK activation that are most relevant for tumor formation and progression have not been fully established.Arguably, the evidence for a clinically valuable anticancer immune response is stronger in MM than any other human malignancy (reviewed in refs. 5-8). Functional T cells restricted to melanoma antigens can be readily recovered from patients with MM, establishing the tumor's immunogenicity in humans (5-7, 9).

BRAFV600E accelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia

“…[7][8][9] MAPK pathway activation in tumor cells without MAPK mutations, such as through Toll-like receptor stimulation or transforming growth factor beta signaling, can promote tumor infiltration and immune suppression at least in part via CD200 and programmed death-ligand 1 (PD-L1) induction, and these effects can be reversed by MEK inhibition. [10][11][12][13] Similar findings are reported in BRAF V600E -mutant melanoma, in which inhibition of BRAF and MEK increases T-cell recognition and dendritic cell function. 14,15 This evidence strongly supports that targeting MAPK signaling in cancer patients could reverse tumor-induced immune suppression, leading to longer disease control, improved resistance to opportunistic infections, and enhanced efficacy of immune-based therapies.…”

“…The above results, together with the immunophenotypic characterization, suggest that the BRAF V600E mutation might accelerate disease development in B-cell leukemia by promoting immune evasion or suppression as observed in some solid tumors, 10,[12][13][14][15]37 rather than simply by affecting proliferation or apoptosis. We therefore examined the effects of B cells expressing BRAF V600E on other immune compartments.…”

Soluble CD200 Is Critical to Engraft Chronic Lymphocytic Leukemia Cells in Immunocompromised Mice

“…Improved understanding of the biology of CLL may help identify other variables predicting which patients may have a poor disease outcome. We have previously shown that CD200, an immunoregulatory molecule overexpressed on a number of solid and systemic tumors, as well as cancer stem cells, played a functional role in suppressing cytotoxic killing of CD200 þ lymphoma and CLL cells (1)(2)(3)(4)(5)(6). Increased expression of CD200R, which is required for signaling mediated following CD200 engagement, was detected on a subpopulation of CD4 þ T cells in the spleen of patients with CLL relative to controls (6).…”

CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor

“…It is thought to reverse the suppression of CD200R-expressing effector cells by blocking CD200 expressed on tumors and is thus restricted to use in the case of CD200-expressing tumors. Indeed, various studies have shown that CD200-expressing tumor cells can suppress T-cell responses in vitro and in vivo (McWhirter et al, 2006;Kretz-Rommel et al, 2007;Petermann et al, 2007;Siva et al, 2008;Pallasch et al, 2009;Wong et al, 2010). Although it is not clear by which mechanism CD200 expression on tumors suppresses the immune system, in vitro studies suggest that blocking CD200-CD200R enhances Th1 responses (McWhirter et al, 2006;Siva et al, 2008).…”