Abstract
Progestagen-associated endometrial protein (PAEP) is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow’s 2.5mm or greater) and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell-secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-γ secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment.
Highlights
Melanoma is one of the most lethal tumors of the skin, responsible for up to 80% of skin cancer deaths [1, 2]
Two pairs of stable melanoma transfectants, 624.38-Mel shPAEP and 624.38-Mel shControl were established using Progestagen-associated endometrial protein (PAEP) lentiviral small hairpin RNA and nontargeting lentiviral shRNA, respectively. 624.38-Mel shPAEP showed an overall knockdown efficiency of over 80% both at the mRNA (Fig. 1A) and protein levels (Fig. 1B)
Melanoma-derived PAEP protein was prepared from the serum-free culture supernatant of PAEP-expressing 624.38-Mel shControl cells, while secreted proteins from PAEP-knockdown 624.38-Mel shPAEP cells were used as a negative control
Summary
Melanoma is one of the most lethal tumors of the skin, responsible for up to 80% of skin cancer deaths [1, 2]. Despite recent exciting advances in the treatment of metastatic melanoma with several newly developed targeted therapies, the majority of patients will still die of their disease. Continued in-depth analysis of the pathogenesis of melanoma is very important in order to identify more effective treatment options. We reported that the oncogenesis and development of melanoma are closely related to the expression level of the protein, PLOS ONE | DOI:10.1371/journal.pone.0119038. Melanoma PAEP Protein Immunosuppresses T Lymphocytes design, data collection and analysis, decision to publish, or preparation of the manuscript We reported that the oncogenesis and development of melanoma are closely related to the expression level of the protein, PLOS ONE | DOI:10.1371/journal.pone.0119038 March 18, 2015
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