Abstract
BackgroundVitiligo 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.MethodsTo 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.ResultsCTL 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.ConclusionsOur data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo.
Highlights
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
Samples were obtained from four different patients with resected stage III or IV melanoma patients under informed consent approved by the institutional review boards of the National Cancer Institute (NCI; Bethesda, Maryland) and the Los Angeles County/University of Southern California; sample analysis was performed under protocols approved by the institutional review board of Stanford University
MART-1 and gp100 specific Cytotoxic T lymphocytes (CTLs) clones were previously isolated from Peripheral blood mononuclear cell (PBMC) samples of four post-vaccinated melanoma patients [15,16,17]
Summary
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. We address whether CTLs respond to and target melanoma cells and normal melanocytes differently. We utilized a set of MART- or gp100-specific CTL clones that were determined to be high, intermediate, or low avidity (recognition efficiency, RE) based on peptide titrations. We assessed both CTL degranulation via mobilization of CD107, an integral membrane protein within cytolytic granules [14,15,16], and target cell killing via chromium release assays. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels
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