Top

Published in:

01-02-2012 | Focussed Research Review

Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation

Authors: Viktor Umansky, Alexandra Sevko

Published in: Cancer Immunology, Immunotherapy | Issue 2/2012

Abstract

Malignant melanoma is known by its rapid progression and poor response to currently applied treatments. Despite the well-documented melanoma immunogenicity, the results of immunotherapeutic clinical trials are not satisfactory. This poor antitumor reactivity is due to the development of chronic inflammation in the tumor microenvironment characterized by infiltrating leukocytes and soluble mediators, which lead to an immunosuppression associated with cancer progression. Using the ret transgenic mouse melanoma model that closely resembles human melanoma, we demonstrated increased levels of chronic inflammatory factors in skin tumors and metastatic lymph nodes, which correlated with tumor progression. Furthermore, Gr1⁺CD11b⁺ myeloid-derived suppressor cells (MDSC), known to block tumor-reactive T cells, were enriched in melanoma lesions and showed an enhanced immunosuppressive capacity. This MDSC accumulation was associated with a strong TCR ζ-chain downregulation in T cells suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon administration of phosphodiesterase-5 inhibitor sildenafil or paclitaxel in non-cytotoxic doses, we observed reduced levels of chronic inflammatory mediators in association with decreased MDSC amounts and immunosuppressive function. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of beneficial outcome of both drugs, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.

MacKie RM, Hauschild A, Eggermont AM (2009) Epidemiology of invasive cutaneous melanoma. Ann Oncol 20(Suppl 6):vi1–vi7PubMedCrossRef

Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Spatz A, Grob JJ, Malvehy J, Newton-Bishop J, Stratigos A, Pehamberger H, Eggermont A (2010) Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. Eur J Cancer 46:270–283PubMedCrossRef

Callahan MK, Wolchok JD, Allison JP (2010) Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol 37:473–484PubMedCrossRef

Pandolfi F, Cianci R, Lolli S, Dunn IS, Newton EE, Haggerty TJ, Boyle LA, Kurnick JT (2008) Strategies to overcome obstacles to successful immunotherapy of melanoma. Int J Immunopathol Pharmacol 21:493–500PubMed

Parmiani G, Castelli C, Santinami M, Rivoltini L (2007) Melanoma immunology: past, present and future. Curr Opin Oncol 19:121–127PubMedCrossRef

Fujii S, Shimizu K, Hemmi H, Steinman RM (2007) Innate Valpha14(+) natural killer T cells mature dendritic cells, leading to strong adaptive immunity. Immunol Rev 220:183–198PubMedCrossRef

Dissemond J, Kothen T, Mörs J, Weimann TK, Lindeke A, Goos M, Wagner SN (2003) Downregulation of tapasin expression in progressive human malignant melanoma. Arch Dermatol Res 295:43–49PubMedCrossRef

Ferrone S, Marincola FM (1995) Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance. Immunol Today 16:487–494PubMedCrossRef

Burke S, Lakshmikanth T, Colucci F, Carbone E (2010) New views on natural killer cell-based immunotherapy for melanoma treatment. Trends Immunol 31:339–345PubMedCrossRef

10.

Ostrand-Rosenberg S (2008) Immune surveillance: a balance between protumor and antitumor immunity. Curr Opin Genet Dev 18:11–18PubMedCrossRef

11.

Lázár-Molnár E, Hegyesi H, Tóth S, Falus A (2000) Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 12:547–554PubMedCrossRef

12.

Antony PA, Restifo NP (2005) CD4⁺CD25⁺ T regulatory cells, immunotherapy of cancer, and interleukin-2. J Immunother 28:120–128PubMedCrossRef

13.

Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263–274PubMedCrossRef

14.

Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174PubMedCrossRef

15.

Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 59:1593–1600PubMedCrossRef

16.

Shurin MR, Naiditch H, Zhong H, Shurin GV (2011) Regulatory dendritic cells: new targets for cancer immunotherapy. Cancer Biol Ther 11:988–992PubMedCrossRef

17.

Ben-Neriah Y, Karin M (2011) Inflammation meets cancer, with NF-κB as the matchmaker. Nat Immunol 12:715–723PubMedCrossRef

18.

Rook GA, Dalgleish A (2011) Infection, immunoregulation, and cancer. Immunol Rev 240:141–159PubMedCrossRef

19.

Cramer DW, Finn OJ (2011) Epidemiologic perspective on immune-surveillance in cancer. Curr Opin Immunol 23:265–271PubMedCrossRef

20.

Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10:369–373PubMedCrossRef

21.

Allavena P, Germano G, Marchesi F, Mantovani A (2011) Chemokines in cancer related inflammation. Exp Cell Res 317:664–673PubMedCrossRef

22.

Baniyash M (2006) Chronic inflammation, immunosuppression and cancer: new insights and outlook. Semin Cancer Biol 16:80–88PubMedCrossRef

23.

Tan TT, Coussens LM (2007) Humoral immunity, inflammation and cancer. Curr Opin Immunol 19:209–216PubMedCrossRef

24.

Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458PubMedCrossRef

25.

Sumimoto H, Imabayashi F, Iwata T, Kawakami Y (2006) The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 203:1651–1656PubMedCrossRef

26.

Haluska F, Pemberton T, Ibrahim N, Kalinsky K (2007) The RTK/RAS/BRAF/PI3K pathways in melanoma: biology, small molecule inhibitors, and potential applications. Semin Oncol 34:546–554PubMedCrossRef

27.

Lomas J, Martin-Duque P, Pons M, Quintanilla M (2008) The genetics of malignant melanoma. Front Biosci 13:5071–5093PubMedCrossRef

28.

Kato M, Takahashi M, Akhand AA, Liu W, Dai Y, Shimizu S, Iwamoto T, Suzuki H, Nakashima I (1999) Transgenic mouse model for skin malignant melanoma. Oncogene 17:1885–1888CrossRef

29.

Eng C (1999) RET proto-oncogene in the development of human cancer. J Clin Oncol 17:380–383PubMed

30.

Umansky V, Abschuetz O, Osen W, Ramacher M, Zhao F, Kato M, Schadendorf D (2008) Melanoma-specific memory T cells are functionally active in ret transgenic mice without macroscopic tumors. Cancer Res 68:9451–9458PubMedCrossRef

31.

Houghton A, Polsky D (2002) Focus on melanoma. Cancer Cell 2:275–278PubMedCrossRef

32.

Zhao F, Falk C, Osen W, Kato M, Schadendorf D, Umansky V (2009) Activation of p38 mitogen-activated protein kinase drives dendritic cells to become tolerogenic in ret transgenic mice spontaneously developing melanoma. Clin Cancer Res 15:4382–4390PubMedCrossRef

33.

Meyer C, Sevko A, Ramacher M, Bazhin AV, Falk CS, Osen W, Borrello I, Kato M, Schadendorf D, Baniyash M, Umansky V (2011) Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci USA 108:17111–17116PubMedCrossRef

34.

Kimpfler S, Sevko A, Ring S, Falk C, Osen W, Frank K, Kato M, Mahnke K, Schadendorf D, Umansky V (2009) Skin melanoma development in ret transgenic mice despite the depletion of CD25+Foxp3+ regulatory T cells in lymphoid organs. J Immunol 183:6330–6337PubMedCrossRef

35.

Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, Dolcetti L, Ugel S, Sonda N, Bicciato S, Falisi E, Calabrese F, Basso G, Zanovello P, Cozzi E, Mandruzzato S, Bronte V (2010) Tumor-induced tolerance and immune suppression depend on the C/EBPb transcription factor. Immunity 32:790–802PubMedCrossRef

36.

Bronstein-Sitton N, Vaknin I, Ezernitchi AV, Leshem B, Halabi A, Houri-Hadad Y, Greenbaum E, Zakay-Rones Z, Shapira L, Baniyash M (2003) Sustained exposure to bacterial antigen induces interferon gamma-dependent T cell receptor zeta down-regulation and impaired T cell function. Nat Immunol 4:957–964PubMedCrossRef

37.

Rössner S, Voigtländer C, Wiethe C, Hänig J, Seifarth C, Lutz MB (2005) Myeloid dendritic cell precursors generated from bone marrow suppress T cell responses via cell contact and nitric oxide production in vitro. Eur J Immunol 35:3533–3544PubMedCrossRef

38.

Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, O’Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, Ramphal R, Gabrilovich DI, Reeves WH, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL (2007) MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med 204:1463–1474PubMedCrossRef

39.

Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V (2010) Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 22:238–244PubMedCrossRef

40.

Bronte V, Zanovello P (2005) Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol 5:641–654PubMedCrossRef

41.

Rodríguez PC, Ochoa AC (2006) T cell dysfunction in cancer: role of myeloid cells and tumor cells regulating amino acid availability and oxidative stress. Semin Cancer Biol 16:66–72PubMedCrossRef

42.

Umansky V, Schirrmacher V (2001) Nitric oxide-induced apoptosis in tumor cells. Adv Cancer Res 82:107–131PubMedCrossRef

43.

Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2:907–916PubMedCrossRef

44.

Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI (2010) Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol 184:3106–3116PubMedCrossRef

45.

Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, De Palma A, Mauri P, Monegal A, Rescigno M, Savino B, Colombo P, Jonjic N, Pecanic S, Lazzarato L, Fruttero R, Gasco A, Bronte V, Viola A (2011) Chemokine nitrosylation prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 208:1949–1962PubMedCrossRef

46.

Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res 70:68–77PubMedCrossRef

47.

Hanson EM, Clements VK, Sinha P, Ilkovitch D, Ostrand-Rosenberg S (2009) Myeloid-derived suppressor cells down-regulate l-selectin expression on CD4⁺ and CD8⁺ T cells. J Immunol 183:937–944PubMedCrossRef

48.

Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmiani G, Rivoltini L (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25:2546–2553PubMedCrossRef

49.

Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R (2010) Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res 70:4335–4345PubMedCrossRef

50.

Ezernitchi AV, Vaknin I, Cohen-Daniel L, Levy O, Manaster E, Halabi A, Pikarsky E, Shapira L, Baniyash M (2006) TCR zeta down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs. J Immunol 177:4763–4772PubMed

51.

Rodríguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC (2002) Regulation of T cell receptor CD3zeta chain expression by l-arginine. J Biol Chem 277:21123–21129PubMedCrossRef

52.

Baniyash M (2004) TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 4:675–687PubMedCrossRef

53.

Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Higashi H, Iwashige H, Aridome K, Hokita S, Aikou T (2002) CD3-zeta chain expression of intratumoral lymphocytes is closely related to survival in gastric carcinoma patients. Cancer 94:1437–1442PubMedCrossRef

54.

Whiteside TL (2004) Down-regulation of zeta-chain expression in T cells: a biomarker of prognosis in cancer? Cancer Immunol Immunother 53:865–878PubMed

55.

Ugel S, Delpozzo F, Desantis G, Papalini F, Simonato F, Sonda N, Zilio S, Bronte V (2009) Therapeutic targeting of myeloid-derived suppressor cells. Curr Opin Pharmacol 9:470–481PubMedCrossRef

56.

Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, Lush RM, Antonia S, Gabrilovich DI (2006) All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 66:9299–9307PubMedCrossRef

57.

Pan PY, Wang GX, Yin B, Ozao J, Ku T, Divino CM, Chen SH (2008) Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood 111:219–228PubMedCrossRef

58.

Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rébé C, Ghiringhelli F (2010) 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 70:3052–3061PubMedCrossRef

59.

Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11:6713–6721PubMedCrossRef

60.

Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I (2006) Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203:2691–2702PubMedCrossRef

61.

De Santo C, Serafini P, Marigo I, Dolcetti L, Bolla M, Del Soldato P, Melani C, Guiducci C, Colombo MP, Iezzi M, Musiani P, Zanovello P, Bronte V (2005) Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc Natl Acad Sci USA 102:4185–4190PubMedCrossRef

62.

Sinha P, Clements VK, Ostrand-Rosenberg S (2005) Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol 174:636–645PubMed

63.

Ghofrani HA, Osterloh IH, Grimminger F (2006) Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 5:689–702PubMedCrossRef

64.

Serafini P, Mgebroff S, Noonan K, Borrello I (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68:5439–5449PubMedCrossRef

65.

Capuano G, Rigamonti N, Grioni M, Freschi M, Bellone M (2009) Modulators of arginine metabolism support cancer immunosurveillance. BMC Immunol 10:1PubMedCrossRef

66.

Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI (2008) Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 205:2235–2249PubMedCrossRef

67.

Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G (2008) Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol 181:4666–4675PubMed

68.

Tartour E, Pere H, Maillere B, Terme M, Merillon N, Taieb J, Sandoval F, Quintin-Colonna F, Lacerda K, Karadimou A, Badoual C, Tedgui A, Fridman WH, Oudard S (2011) Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 30:83–95PubMedCrossRef

69.

Laties A, Zrenner E (2002) Viagra (sildenafil citrate) and ophthalmology. Prog Retin Eye Res 21:485–506PubMedCrossRef

70.

Nowak AK, Lake RA, Robinson BW (2006) Combined chemoimmunotherapy of solid tumours: improving vaccines? Adv Drug Deliv Rev 58:975–990PubMedCrossRef

71.

Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8:151–160PubMedCrossRef

72.

Kaneno R, Shurin GV, Kaneno FM, Naiditch H, Luo J, Shurin MR (2011) Chemotherapeutic agents in low non-cytotoxic concentrations increase immunogenicity of human colon cancer cells. Cell Oncol (Dordr) 34:97–106

73.

Kaneno R, Shurin GV, Tourkova IL, Shurin MR (2009) Chemomodulation of human dendritic cell function by anti-neoplastic agents in low non-cytotoxic concentrations. J Transl Med 7:58PubMedCrossRef

74.

Shurin GV, Tourkova IL, Kaneno R, Shurin MR (2009) Chemotherapeutic agents in non-cytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism. J Immunol 183:137–144PubMedCrossRef

75.

Shurin GV, Tourkova IL, Shurin MR (2008) Low-dose chemotherapeutic agents regulate small rho GTPase activity in dendritic cells. J Immunother 31:491–499PubMedCrossRef

76.

Zhong H, Han B, Tourkova IL, Lokshin A, Rosenbloom A, Shurin MR, Shurin GV (2007) Low-dose paclitaxel prior to intratumoral dendritic cell vaccine modulates intratumoral cytokine network and lung cancer growth. Clin Cancer Res 13:5455–5462PubMedCrossRef

Title: Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation
Authors: Viktor Umansky
Alexandra Sevko
Publication date: 01-02-2012
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 2/2012
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1164-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

ACC 2024 Congress

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2012

From cell regulation to patient survival: 2nd Cancer immunotherapy and immunomonitoring (CITIM) meeting, Budapest, 2–5 May 2011

Exposure of CD34+ precursors to cytostatic anthraquinone-derivatives induces rapid dendritic cell differentiation: implications for cancer immunotherapy

Immune suppression in the tumor microenvironment: a role for dendritic cell-mediated tolerization of T cells

Potential rescue, survival and differentiation of cancer stem cells and primary non-transformed stem cells by monocyte-induced split anergy in natural killer cells

Regulatory dendritic cells in the tumor immunoenvironment

Expression of anti-HVEM single-chain antibody on tumor cells induces tumor-specific immunity with long-term memory

Keynote webinar | Spotlight on antibody–drug conjugates in cancer