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Melan-A/MART-1-Specific CD4 T Cells in Melanoma Patients: Identification of New Epitopes and Ex Vivo Visualization of Specific T Cells by MHC Class II Tetramers¹

Gilles Bioley^*, Camilla Jandus^*, Sandra Tuyaerts, Donata Rimoldi, William W. Kwok, Daniel E. Speiser^*,¶, Jean-Marie Tiercy^||, Kris Thielemans, Jean-Charles Cerottini and Pedro Romero^2,*,¶

^* Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, University Hospital, Lausanne, Switzerland; Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School, Vrije Universiteit, Brussels, Belgium; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; Benaroya Research Institute at Virginia Mason, Seattle, WA 98101; ^¶ National Center for Competence in Research, Molecular Oncology, Epalinges, Switzerland; and ^|| National Reference Laboratory for Histocompatibility, Transplantation Immunology Unit, Division of Immunology and Allergology, University Hospital, Geneva, Switzerland

Over the past decade, many efforts have been made to identify MHC class II-restricted epitopes from different tumor-associated Ags. Melan-A/MART-1_26–35 parental or Melan-A/MART-1_{26–35(A27L)} analog epitopes have been widely used in melanoma immunotherapy to induce and boost CTL responses, but only one Th epitope is currently known (Melan-A_51–73, DRB1*0401 restricted). In this study, we describe two novel Melan-A/MART-1-derived sequences recognized by CD4 T cells from melanoma patients. These epitopes can be mimicked by peptides Melan-A_27–40 presented by HLA-DRB1*0101 and HLA-DRB1*0102 and Melan-A_25–36 presented by HLA-DQB1*0602 and HLA-DRB1*0301. CD4 T cell clones specific for these epitopes recognize Melan-A/MART-1⁺ tumor cells and Melan-A/MART-1-transduced EBV-B cells and recognition is reduced by inhibitors of the MHC class II presentation pathway. This suggests that the epitopes are naturally processed and presented by EBV-B cells and melanoma cells. Moreover, Melan-A-specific Abs could be detected in the serum of patients with measurable CD4 T cell responses specific for Melan-A/MART-1. Interestingly, even the short Melan-A/MART-1_{26–35(A27L)} peptide was recognized by CD4 T cells from HLA-DQ6⁺ and HLA-DR3⁺ melanoma patients. Using Melan-A/MART-1_25–36/DQ6 tetramers, we could detect Ag-specific CD4 T cells directly ex vivo in circulating lymphocytes of a melanoma patient. Together, these results provide the basis for monitoring of naturally occurring and vaccine-induced Melan-A/MART-1-specific CD4 T cell responses, allowing precise and ex vivo characterization of responding T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the National Center for Competence in Research Molecular Oncology. G.B. was funded in part by the Muschamp Foundation. C.J. was supported by Fond National Suisse Oncosuisse.

² Address correspondence and reprint requests to Dr. Pedro Romero, Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique Niveau. 5-aile est, Avenue. Pierre Decker 4, 1005 Lausanne, Switzerland. E-mail address: pedro.romero{at}isrec.unil.ch

³ Abbreviations used in this paper: TAA, tumor-associated Ag; EBV-B, EBV-transformed B; RT, room temperature; PI, propidium iodide.

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