PTEN Functions as a Melanoma Tumor Suppressor by Promoting Host Immune Response

Oncogene. 2014 Sep 18;33(38):4632-42. doi: 10.1038/onc.2013.409. Epub 2013 Oct 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune Tolerance
  • Melanoma / immunology*
  • Melanoma / metabolism
  • PTEN Phosphohydrolase / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • STAT3 Transcription Factor / metabolism
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / metabolism
  • Transcriptional Activation
  • Tumor Escape

Substances

  • Cytokines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Phosphatidylinositol 3-Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human