Identification of DRG-1 As a Melanoma-Associated Antigen Recognized by CD4+ Th1 Cells.

Yukiko Kiniwa,Mingjun Wang,Chuang Sun,Jeffrey E Lee,Rong-Fu Wang,Jiang Li,Helen Y Wang,Xue-Feng Bai

doi:10.1371/journal.pone.0124094

Yukiko Kiniwa, Mingjun Wang + Show 6 more

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https://doi.org/10.1371/journal.pone.0124094

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Abstract

Immunotherapy has emerged as a promising strategy for the treatment of metastatic melanoma. Clinical studies have demonstrated the feasibility of cancer immunotherapy using tumor antigens recognized by CD8+ T cells. However, the overall immune responses induced by these antigens are too weak and transient to induce tumor regression in the majority of patients who received immunization. A growing body of evidence suggests that CD4+ T helper (Th) cells play an important role in antitumor immunity. Therefore, the identification of MHC class II-restricted tumor antigens capable of stimulating CD4+ T cells may provide opportunities for developing effective cancer vaccines. To this end, we describe the identification of developmentally regulated GTP-binding protein 1 (DRG-1) as a melanoma-associated antigen recognized by HLA-DR11-restricted CD4+ Th1 cells. Epitope mapping analysis showed that the DRG1248-268 epitope of DRG-1 was required for T cell recognition. Reverse transcription-polymerase chain reaction revealed that DRG-1 was highly expressed in melanoma cell lines but not in normal tissues. DRG-1 knockdown by lentiviral-based shRNA suppressed melanoma cell proliferation and soft agar colony formation. Taken together, these data suggest that DRG-1 plays an important role in melanoma cell growth and transformation, indicating that DRG1 may represent a novel target for CD4+ T cell-mediated immunotherapy in melanoma.

Highlights

Melanoma is the most aggressive form of skin cancer, with metastatic disease occurring in 10%–15% of patients at diagnosis [1], and is continuing to be a major health concern
The activity of TIL155-C1 T cells against autologous tumor cells was blocked by antiMHC class II and anti-HLA-DR monoclonal antibodies, but not by an anti-MHC class I antibody (Fig 1B)
TIL155-C1 and TIL155-C2 secreted granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-2, and IFN-γ but did not secrete IL4, IL-10, or transforming growth factor (TGF)-β after exposure to 155mel tumor cells (Fig 1C). These findings suggested that the TIL155 T cell clones were CD4+ Th1 cells, and their antigen specificity was either HLA-DRÃ0101- or HLA-DRÃ1101-restricted

Summary

Introduction

Melanoma is the most aggressive form of skin cancer, with metastatic disease occurring in 10%–15% of patients at diagnosis [1], and is continuing to be a major health concern. The National Cancer Institute estimates that 76,100 Americans will be diagnosed with melanoma, and 9,710 will die from the disease in 2014. Metastatic melanoma has a dismal prognosis; the 5-year survival rates plummet from 98.2% for patients with localized disease to 61.7% and 15.2% for individuals with regional and distant metastases, respectively [2]. CD4+ Th1 Cells Recognize DRG-1 Antigen therapeutic options for metastatic melanoma are limited by low efficacy rates, toxic side effects, and drug resistance development [1,3,4]. New therapeutic strategies are urgently needed for the treatment of metastatic melanoma

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