Cytotoxic T lymphocyte responses against melanocytes and melanoma
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RESEARCH
Open Access
Cytotoxic T lymphocyte responses against melanocytes and melanoma Gwendolen Y Chang1, Holbrook E Kohrt1, Tor B Stuge1, Erich J Schwartz2, Jeffrey S Weber3 and Peter P Lee1*
Abstract Background: Vitiligo is a common toxicity associated with immunotherapy for melanoma. Cytotoxic T lymphocytes (CTLs) against melanoma commonly target melanoma-associated antigens (MAAs) which are also expressed by melanocytes. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels. Methods: To understand the dichotomous role of MAA-specific CTL, we characterized the functional reactivities of established CTL clones directed to MAAs against melanoma and melanocyte cell lines. Results: CTL clones generated from melanoma patients were capable of eliciting MHC-restricted, MAA-specific lysis against melanocyte cell lines as well as melanoma cells. Among the tested HLA-A*0201-restricted CTL clones, melanocytes evoked equal to slightly higher degranulation and cytolytic responses as compared to melanoma cells. Moreover, MAA-specific T cells from vaccinated patients responded directly ex vivo to melanoma and melanocytes. Melanoma cells express slightly higher levels of MART-1 and gp100 than melanocytes as measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry. Conclusions: Our data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo.
Introduction Recent FDA approval of ipilimumab for metastatic melanoma provides strong support for the ability of the immune system to mediate a beneficial effect against this disease. However, immunotherapies for melanoma, including ipilimumab [1] and adoptive cellular therapies [2], come with substantial toxicities, including vitiligo [3-5], ocular [6] and systemic autoimmunity [1]. As such, a major need in next-generation melanoma immunotherapy is to uncouple tumor immunity from autoimmunity [7]. To improve the functional effectiveness of melanoma-reactive CTLs, understanding the factors leading to recognition of self and the barriers to breaking immune tolerance is crucial. Two decades ago, pioneering work from the Rosenberg [8] and Boon [9] groups first demonstrated that T cells infiltrating human melanoma often target self, nonmutated proteins that are also expressed by normal * Correspondence: [email protected] 1 Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA Full list of author information is available at the end of the article
melanocytes. These include enzymes in the biosynthesis of melanin, such as MART-1, gp100, and tyrosinase [10]. How these self tumor-associated antigens (TAAs) elicit T cell responses in the context of melanoma remains unclear. It is suggested that TAAs are overexpressed in melanoma cells, thus eliciting responses by low avidity TAA-specific T cells that escape central deletion [11,12]. If true, this offers a
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