title: PTEN functions as a melanoma tumor suppressor by promoting host immune response.
abstract: Cancer cells acquire several traits that allow for their survival and progression, including the ability to evade the host immune response. However, the mechanisms by which cancer cells evade host immune responses remain largely elusive. Here we study the phenomena of immune evasion in malignant melanoma cells. We find that the tumor suppressor phosphatase and tensin homolog (PTEN) is an important regulator of the host immune response against melanoma cells. Mechanistically, PTEN represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositide 3-kinase (PI3K) pathway. In melanoma cells lacking PTEN, signal transducer and activator of transcription 3 activates the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Furthermore, conditioned media from PTEN-deficient, patient-derived short-term melanoma cultures and established melanoma cell lines blocked the production of the interleukin-12 (IL-12) in human monocyte-derived dendritic cells. Inhibition of IL-12 production was rescued by restoring PTEN or using neutralizing antibodies against the immunosuppressive cytokines. Furthermore, we report that PTEN, as an alternative mechanism to promote the host immune response against cancer cells, represses the expression of programmed cell death 1 ligand, a known repressor of the host immune response. Finally, to establish the clinical significance of our results, we analyzed malignant melanoma patient samples with or without brisk host responses. These analyses confirmed that PTEN loss is associated with a higher percentage of malignant melanoma samples with non-brisk host responses compared with samples with brisk host responses. Collectively, these results establish that PTEN functions as a melanoma tumor suppressor in part by regulating the host immune response against melanoma cells and highlight the importance of assessing PTEN status before recruiting melanoma patients for immunotherapies.
authors.affiliation: 1] Department of Pathology, Yale University School of Medicine, New Haven, CT, USA [2] Department of Oral and Maxillofacial Surgery, College of Stomatology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: J-Ae
authors.initials: JA
authors.lastname: Richards
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Aung
authors.affiliation: Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Emley
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kluger
authors.affiliation: Singapore Institute of Clinical Sciences, Agency for Science Technology and Research (A*STAR), Brenner Center for Molecular Medicine, Singapore, Singapore.
authors.forename: S K
authors.initials: SK
authors.lastname: Dogra
authors.affiliation: Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mahalingam
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: N
authors.initials: N
authors.lastname: Wajapeyee
mesh_terms: D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007108:Immune Tolerance; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism; D015533:Transcriptional Activation; D019139:Tumor Escape
chemical_list: D016207:Cytokines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human