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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275: 1943–1947.
Wu H, Goel V, Haluska FG . PTEN signaling pathways in melanoma. Oncogene 2003; 22: 3113–3122.
Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 2009; 41: 544–552.
Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 2009; 15: 294–303.
Nogueira C, Kim KH, Sung H, Paraiso KH, Dannenberg JH, Bosenberg M et al. Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis. Oncogene 2010; 29: 6222–6232.
Lowe SW, Cepero E, Evan G . Intrinsic tumour suppression. Nature 2004; 432: 307–315.
Burikhanov R, Zhao Y, Goswami A, Qiu S, Schwarze SR, Rangnekar VM . The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 2009; 138: 377–388.
Zitvogel L, Tesniere A, Kroemer G . Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 2006; 6: 715–727.
Cozar JM, Aptsiauri N, Tallada M, Garrido F, Ruiz-Cabello F . Late pulmonary metastases of renal cell carcinoma immediately after post-transplantation immunosuppressive treatment: a case report. J Med Case Rep 2008; 2: 111.
Lengagne R, Graff-Dubois S, Garcette M, Renia L, Kato M, Guillet JG et al. Distinct role for CD8 T cells toward cutaneous tumors and visceral metastases. J Immunol 2008; 180: 130–137.
O'Shea JJ, Ma A, Lipsky P . Cytokines and autoimmunity. Nat Rev Immunol 2002; 2: 37–45.
Alcocer-Gonzalez JM, Berumen J, Tamez-Guerra R, Bermudez-Morales V, Peralta-Zaragoza O, Hernandez-Pando R et al. In vivo expression of immunosuppressive cytokines in human papillomavirus-transformed cervical cancer cells. Viral Immunol 2006, Summer 19: 481–491.
Rabinovich GA, Gabrilovich D, Sotomayor EM . Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 2007; 25: 267–296.
Salmena L, Carracedo A, Pandolfi PP . Tenets of PTEN tumor suppression. Cell 2008; 133: 403–414.
Li N, Grivennikov SI, Karin M . The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell. 2011; 19: 429–431.
Caamano J, Hunter CA . NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions. Clin Microbiol Rev 2002; 15: 414–429.
Khalaf H, Jass J, Olsson PE . Differential cytokine regulation by NF-kappaB and AP-1 in Jurkat T-cells. BMC Immunol 2010; 11: 26.
Hart JR, Liao L, Yates JR 3rd, Vogt PK . Essential role of Stat3 in PI3K-induced oncogenic transformation. Proc Natl Acad Sci USA 2011; 108: 13247–13252.
Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP, Baldwin AS . Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev 2008; 22: 1490–1500.
Loots GG, Ovcharenko I . rVISTA 2.0: evolutionary analysis of transcription factor binding sites. Nucleic Acids Res 2004; 32 (Web Server issue): W217–W221.
Cimica V, Chen HC, Iyer JK, Reich NC . Dynamics of the STAT3 transcription factor: nuclear import dependent on Ran and importin-beta1. PLoS One 2011; 6: e20188.
Liu L, McBride KM, Reich NC . STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3. Proc Natl Acad Sci USA 2005; 102: 8150–8155.
Lund TC, Coleman C, Horvath E, Sefton BM, Jove R, Medveczky MM et al. The Src-family kinase Lck can induce STAT3 phosphorylation and DNA binding activity. Cell Signal 1999; 11: 789–796.
Blank C, Mackensen A . Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother 2007; 56: 739–745.
Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007; 13: 84–88.
Sumimoto H, Imabayashi F, Iwata T, Kawakami Y . The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 2006; 203: 1651–1656.
Donia M, Fagone P, Nicoletti F, Andersen RS, Hogdall E, Straten PT et al. BRAF inhibition improves tumor recognition by the immune system: potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer. Oncoimmunology 2012; 1: 1476–1483.
Knight DA, Ngiow SF, Li M, Parmenter T, Mok S, Cass A et al. Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J Clin Invest 2013; 123: 1371–1381.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949–954.
Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM et al. High frequency of BRAF mutations in nevi. Nat Genet 2003; 33: 19–20.
Rosso R, Romagosa Y, Kirsner RS . Progression of NRAS and BRAF mutations in cutaneous melanoma. J Invest Dermatol 2009; 129: 1318.
Greene VR, Johnson MM, Grimm EA, Ellerhorst JA . Frequencies of NRAS and BRAF mutations increase from the radial to the vertical growth phase in cutaneous melanoma. J Invest Dermatol 2009; 129: 1483–1488.
Witten IH, Frank E, Hall MA . Data Mining: Practical Machine Learning Tools and Techniques 3rd edn Morgan Kaufmann, Burlington, MA, 2011, xxxiii, 629 p. p.
Zitvogel L, Tesniere A, Kroemer G . Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 2006; 6: 715–727.
Tsao H, Mihm MC Jr., Sheehan C . PTEN expression in normal skin, acquired melanocytic nevi, and cutaneous melanoma. J Am Acad Dermatol 2003; 49: 865–872.
Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR . Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 2008; 132: 363–374.
Santra MK, Wajapeyee N, Green MR . F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage. Nature 2009; 459: 722–725.
Brandl C, Ortler S, Herrmann T, Cardell S, Lutz MB, Wiendl H . B7-H1-deficiency enhances the potential of tolerogenic dendritic cells by activating CD1d-restricted type II NKT cells. PLoS One 2010; 5: e10800.
Dadzie OE, Yang S, Emley A, Keady M, Bhawan J, Mahalingam M . RAS and RAF mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis. Br J Dermatol 2009; 160: 368–375.
Mihm MC Jr., Clemente CG, Cascinelli N . Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab Invest 1996; 74: 43–47.
Nguyen LT, Yen PH, Nie J, Liadis N, Ghazarian D, Al-Habeeb A et al. Expansion and characterization of human melanoma tumor-infiltrating lymphocytes (TILs). PLoS One 2010; 5: e13940.
Acknowledgements
NW is a Sidney Kimmel Scholar for translational Cancer research and is supported by a team science award from Melanoma Research Alliance and a Career Development Award from Melanoma Research Foundation. NW and YK are members of the Yale Cancer Center.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Dong, Y., Richards, JA., Gupta, R. et al. PTEN functions as a melanoma tumor suppressor by promoting host immune response. Oncogene 33, 4632–4642 (2014). https://doi.org/10.1038/onc.2013.409
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2013.409
Keywords
This article is cited by
-
Neutrophil-to-lymphocyte ratio is a prognostic factor reflecting immune condition of tumor microenvironment in squamous cell lung cancer
Scientific Reports (2024)
-
Evolving therapeutic landscape of advanced hepatocellular carcinoma
Nature Reviews Gastroenterology & Hepatology (2023)
-
AKR1B10 accelerates the production of proinflammatory cytokines via the NF-κB signaling pathway in colon cancer
Journal of Molecular Histology (2022)
-
USP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade
Nature Communications (2021)
-
Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment
British Journal of Cancer (2021)