Cancer Immunology, Immunotherapy

, Volume 61, Issue 9, pp 1511–1520

The roles of mast cells in anticancer immunity

Symposium-in-writing paper

Abstract

The tumor microenvironment (TME), which is composed of stromal cells such as endothelial cells, fibroblasts, and immune cells, provides a supportive niche promoting the growth and invasion of tumors. The TME also raises an immunosuppressive barrier to effective antitumor immune responses and is therefore emerging as a target for cancer immunotherapies. Mast cells (MCs) accumulate in the TME at early stages, and their presence in the TME is associated with poor prognosis in many aggressive human cancers. Some well-established roles of MCs in cancer are promoting angiogenesis and tumor invasion into surrounding tissues. Several mouse models of inducible and spontaneous cancer show that MCs are among the first immune cells to accumulate within and shape the TME. Although MCs and other suppressive myeloid cells are associated with poor prognosis in human cancers, high densities of intratumoral T effector (Teff) cells are associated with a favorable prognosis. The latter finding has stimulated interest in developing therapies to increase intratumoral T cell density. However, cellular and molecular mechanisms promoting high densities of intratumoral Teff cells within the TME are poorly understood. New evidence suggests that MCs are essential for shaping the immune-suppressive TME and impairing both antitumor Teff cell responses and intratumoral T cell accumulation. These roles for MCs warrant further elucidation in order to improve antitumor immunity. Here, we will summarize clinical studies of the prognostic significance of MCs within the TME in human cancers, as well as studies in mouse models of cancer that reveal how MCs are recruited to the TME and how MCs facilitate tumor growth. Also, we will summarize our recent studies indicating that MCs impair generation of protective antitumor T cell responses and accumulation of intratumoral Teff cells. We will also highlight some approaches to target MCs in the TME in order to unleash antitumor cytotoxicity.

Keywords

Mast cells Cancer Tumor microenvironment T cells AllergoOncology Symposium-in-Writing 

References

  1. 1.
    Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331(6024):1565–1570. doi:10.1126/science.1203486 PubMedCrossRefGoogle Scholar
  2. 2.
    Galli SJ, Maurer M, Lantz CS (1999) Mast cells as sentinels of innate immunity. Curr Opin Immunol 11(1):53–59. doi:10.1016/S0952-7915(99)80010-7 PubMedCrossRefGoogle Scholar
  3. 3.
    Galli SJ, Grimbaldeston M, Tsai M (2008) Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 8(6):478–486. doi:10.1038/nri2327 PubMedCrossRefGoogle Scholar
  4. 4.
    Lu LF, Lind EF, Gondek DC et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002. doi:10.1038/nature05010 PubMedCrossRefGoogle Scholar
  5. 5.
    Beer TW, Ng LB, Murray K (2008) Mast cells have prognostic value in Merkel cell carcinoma. Am J Dermatopathol 30(1):27–30. doi:10.1097/DAD.0b013e31815c932a PubMedCrossRefGoogle Scholar
  6. 6.
    Ribatti D, Ennas MG, Vacca A, Ferreli F, Nico B, Orru S, Sirigu P (2003) Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Invest 33(5):420–425PubMedCrossRefGoogle Scholar
  7. 7.
    Duncan LM, Richards LA, Mihm MC Jr (1998) Increased mast cell density in invasive melanoma. J Cutan Pathol 25(1):11–15PubMedCrossRefGoogle Scholar
  8. 8.
    Molin D, Edstrom A, Glimelius I, Glimelius B, Nilsson G, Sundstrom C, Enblad G (2002) Mast cell infiltration correlates with poor prognosis in Hodgkin’s lymphoma. Br J Haematol 119(1):122–124. doi:10.1111/j.1600-0560 PubMedCrossRefGoogle Scholar
  9. 9.
    Gounaris E, Erdman SE, Restaino C, Gurish MF, Friend DS, Gounari F, Lee DM, Zhang G, Glickman JN, Shin K, Rao VP, Poutahidis T, Weissleder R, McNagny KM, Khazaie K (2007) Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci USA 104(50):19977–19982. doi:10.1073/pnas.0704620104 PubMedCrossRefGoogle Scholar
  10. 10.
    Acikalin MF, Oner U, Topcu I, Yasar B, Kiper H, Colak E (2005) Tumour angiogenesis and mast cell density in the prognostic assessment of colorectal carcinomas. Dig Liver Dis 37(3):162–169. doi:10.1016/j.dld.2004.09.028 PubMedCrossRefGoogle Scholar
  11. 11.
    Gulubova M, Vlaykova T (2009) Prognostic significance of mast cell number and microvascular density for the survival of patients with primary colorectal cancer. J Gastroenterol Hepatol 24(7):1265–1275. doi:10.1111/j.1440-1746.2007.05009.x PubMedCrossRefGoogle Scholar
  12. 12.
    Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F, Bevilacqua G, Campani D (2004) Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 57(6):630–636PubMedCrossRefGoogle Scholar
  13. 13.
    Cai SW, Yang SZ, Gao J, Pan K, Chen JY, Wang YL, Wei LX, Dong JH (2011) Prognostic significance of mast cell count following curative resection for pancreatic ductal adenocarcinoma. Surgery 149(4):576–584. doi:10.1016/j.surg.2010.10.009 PubMedCrossRefGoogle Scholar
  14. 14.
    Strouch MJ, Cheon EC, Salabat MR, Krantz SB, Gounaris E, Melstrom LG, Dangi-Garimella S, Wang E, Munshi HG, Khazaie K, Bentrem DJ (2010) Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clin Cancer Res 16(8):2257–2265. doi:10.1158/1078-0432.CCR-09-1230 PubMedCrossRefGoogle Scholar
  15. 15.
    Rajput ABTD, Cheang MC, Voduc DK, Leung S, Gelmon KA, Gilks CB, Huntsman DG (2008) Stromal mast cells in invasive breast cancer are a marker of favorable prognosis: a study of 4,444 cases. Breast Cancer Res Treat 107(2):249–257PubMedCrossRefGoogle Scholar
  16. 16.
    della Rovere F, Granata A, Familiari D, D’Arrigo G, Mondello B, Basile G (2007) Mast cells in invasive ductal breast cancer: different behavior in high and minimum hormone-receptive cancers. Anticancer Res 27(4B):2465–2471PubMedGoogle Scholar
  17. 17.
    Gooch JL, Lee AV, Yee D (1998) Interleukin 4 inhibits growth and induces apoptosis in human breast cancer cells. Cancer Res 58(18):4199–4205PubMedGoogle Scholar
  18. 18.
    Johansson A, Rudolfsson S, Hammarsten P, Halin S, Pietras K, Jones J, Stattin P, Egevad L, Granfors T, Wikstrom P, Bergh A (2010) Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy. Am J Pathol 177(2):1031–1041. doi:10.2353/ajpath.2010.100070 PubMedCrossRefGoogle Scholar
  19. 19.
    Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P (2005) Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 23(35):8959–8967. doi:10.1200/JCO.2005.01.4910 PubMedCrossRefGoogle Scholar
  20. 20.
    Huang B, Lei Z, Zhang GM et al (2008) SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood 112(4):1269–1279PubMedCrossRefGoogle Scholar
  21. 21.
    Grimbaldeston MA, Chen CC, Piliponsky AM et al (2005) Mast cell-deficient W-sash c-kit mutant KitW-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 167(3):835–848PubMedCrossRefGoogle Scholar
  22. 22.
    Wolters PJ, Mallen-St Clair J, Lewis CC, Villalta SA, Baluk P, Erle DJ, Caughey GH (2005) Tissue-selective mast cell reconstitution and differential lung gene expression in mast cell-deficient Kit(W-sh)/Kit(W-sh) sash mice. Clin Exp Allergy 35(1):82–88. doi:10.1111/j.1365-2222.2005.02136.x PubMedCrossRefGoogle Scholar
  23. 23.
    Coussens LM, Raymond WW, Bergers G et al (1999) Inflammatory cells up-regualate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13:1382–1397PubMedCrossRefGoogle Scholar
  24. 24.
    Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI (2007) Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13(10):1211–1218. doi:10.1038/nm1649 PubMedCrossRefGoogle Scholar
  25. 25.
    Gounaris E, Erdman S, Restaino C et al (2007) Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci U S A 104:19977–19982PubMedCrossRefGoogle Scholar
  26. 26.
    de Vries VC, Wasiuk A, Bennett KA, Benson MJ, Elgueta R, Waldschmidt TJ, Noelle RJ (2009) Mast cell degranulation breaks peripheral tolerance. Am J Transplant 9(10):2270–2280. doi:10.1111/j.1600-6143.2009.02755.x PubMedCrossRefGoogle Scholar
  27. 27.
    de Vries VC, Pino-Lagos K, Nowak EC, Bennett KA, Oliva C, Noelle RJ (2011) Mast cells condition dendritic cells to mediate allograft tolerance. Immunity 35(4):550–561. doi:10.1016/j.immuni.2011.09.012 PubMedCrossRefGoogle Scholar
  28. 28.
    Oldford SA, Haidl ID, Howatt MA, Leiva CA, Johnston B, Marshall JS (2010) A critical role for mast cells and mast cell-derived IL-6 in TLR2-mediated inhibition of tumor growth. J Immunol 185(11):7067–7076. doi:10.4049/jimmunol.1001137 PubMedCrossRefGoogle Scholar
  29. 29.
    Jensen-Jarolim E, Achatz G, Turner MC, Karagiannis S, Legrand F, Capron M, Penichet ML, Rodriguez JA, Siccardi AG, Vangelista L, Riemer AB, Gould H (2008) AllergoOncology: the role of IgE-mediated allergy in cancer. Allergy 63(10):1255–1266. doi:10.1111/j.1398-9995.2008.01768.x PubMedCrossRefGoogle Scholar
  30. 30.
    Reali E, Greiner JW, Corti A, Gould HJ, Bottazzoli F, Paganelli G, Schlom J, Siccardi AG (2001) IgEs targeted on tumor cells: therapeutic activity and potential in the design of tumor vaccines. Cancer Res 61(14):5517–5522PubMedGoogle Scholar
  31. 31.
    Gould HJ, Mackay GA, Karagiannis SN, O’Toole CM, Marsh PJ, Daniel BE, Coney LR, Zurawski VR Jr, Joseph M, Capron M, Gilbert M, Murphy GF, Korngold R (1999) Comparison of IgE and IgG antibody-dependent cytotoxicity in vitro and in a SCID mouse xenograft model of ovarian carcinoma. Eur J Immunol 29(11):3527–3537. doi:10.1002/(SICI)1521-4141(199911)29:11<3527:AID-IMMU3527>3.0.CO;2-5 PubMedCrossRefGoogle Scholar
  32. 32.
    Bramswig KH, Knittelfelder R, Gruber S, Untersmayr E, Riemer AB, Szalai K, Horvat R, Kammerer R, Zimmermann W, Zielinski CC, Scheiner O, Jensen-Jarolim E (2007) Immunization with mimotopes prevents growth of carcinoembryonic antigen positive tumors in BALB/c mice. Clin Cancer Res 13(21):6501–6508. doi:10.1158/1078-0432.CCR-07-0692 PubMedCrossRefGoogle Scholar
  33. 33.
    Riemer AB, Jensen-Jarolim E (2007) Mimotope vaccines: epitope mimics induce anti-cancer antibodies. Immunol Lett 113(1):1–5. doi:10.1016/j.imlet.2007.07.008 PubMedCrossRefGoogle Scholar
  34. 34.
    Riemer AB, Untersmayr E, Knittelfelder R, Duschl A, Pehamberger H, Zielinski CC, Scheiner O, Jensen-Jarolim E (2007) Active induction of tumor-specific IgE antibodies by oral mimotope vaccination. Cancer Res 67(7):3406–3411. doi:10.1158/0008-5472.CAN-06-3758 PubMedCrossRefGoogle Scholar
  35. 35.
    Camus M, Tosolini M, Mlecnik B, Pages F, Kirilovsky A, Berger A, Costes A, Bindea G, Charoentong P, Bruneval P, Trajanoski Z, Fridman WH, Galon J (2009) Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res 69(6):2685–2693. doi:10.1158/0008-5472.CAN-08-2654 PubMedCrossRefGoogle Scholar
  36. 36.
    Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77(7):1303–1310. doi:10.1002/(SICI)1097-0142(19960401)77:7<1303:AID-CNCR12>3.0.CO;2-5 PubMedCrossRefGoogle Scholar
  37. 37.
    Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman WH, Cadranel J (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26(27):4410–4417. doi:10.1200/JCO.2007.15.0284 PubMedCrossRefGoogle Scholar
  38. 38.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964. doi:10.1126/science.1129139 PubMedCrossRefGoogle Scholar
  39. 39.
    Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58(16):3491–3494PubMedGoogle Scholar
  40. 40.
    Ryschich E, Notzel T, Hinz U, Autschbach F, Ferguson J, Simon I, Weitz J, Frohlich B, Klar E, Buchler MW, Schmidt J (2005) Control of T-cell-mediated immune response by HLA class I in human pancreatic carcinoma. Clin Cancer Res 11(2 Pt 1):498–504. doi:10.1034/j.1399-0039.2003 PubMedGoogle Scholar
  41. 41.
    Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543. doi:10.1073/pnas.0509182102 PubMedCrossRefGoogle Scholar
  42. 42.
    Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213. doi:10.1056/NEJMoa020177 PubMedCrossRefGoogle Scholar
  43. 43.
    Griffioen AW (2008) Anti-angiogenesis: making the tumor vulnerable to the immune system. Cancer Immunol Immunother 57(10):1553–1558. doi:10.1007/s00262-008-0524-3 PubMedCrossRefGoogle Scholar
  44. 44.
    Motz GT, Coukos G (2011) The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol 11(10):702–711. doi:10.1038/nri3064 PubMedCrossRefGoogle Scholar
  45. 45.
    Muller WA (2011) Mechanisms of leukocyte transendothelial migration. Annu Rev Pathol 6:323–344. doi:10.1146/annurev-pathol-011110-130224 PubMedCrossRefGoogle Scholar
  46. 46.
    Dirkx AE, Oude Egbrink MG, Kuijpers MJ, van der Niet ST, Heijnen VV, Bouma-ter Steege JC, Wagstaff J, Griffioen AW (2003) Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res 63(9):2322–2329PubMedGoogle Scholar
  47. 47.
    Dirkx AE, oude Egbrink MG, Castermans K, van der Schaft DW, Thijssen VL, Dings RP, Kwee L, Mayo KH, Wagstaff J, Bouma-ter Steege JC, Griffioen AW (2006) Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB J 20(6):621–630. doi:10.1096/fj.05-4493com PubMedCrossRefGoogle Scholar
  48. 48.
    Manning EA, Ullman JG, Leatherman JM, Asquith JM, Hansen TR, Armstrong TD, Hicklin DJ, Jaffee EM, Emens LA (2007) A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res 13(13):3951–3959. doi:10.1158/1078-0432.CCR-07-0374 PubMedCrossRefGoogle Scholar
  49. 49.
    Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA (2010) Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 70(15):6171–6180. doi:10.1158/0008-5472.CAN-10-0153 PubMedCrossRefGoogle Scholar
  50. 50.
    Patel D, Bassi R, Hooper AT, Sun H, Huber J, Hicklin DJ, Kang X (2008) Enhanced suppression of melanoma tumor growth and metastasis by combined therapy with anti-VEGF receptor and anti-TYRP-1/gp75 monoclonal antibodies. Anticancer Res 28(5A):2679–2686PubMedGoogle Scholar
  51. 51.
    Galli SJ, Nakae S, Tsai M (2005) Mast cells in the development of adaptive immune responses. Nat Immunol 6:135–142PubMedCrossRefGoogle Scholar
  52. 52.
    Gosset P, Bureau F, Angeli V et al (2003) Prostaglandin D2 affects the maturation of human monocyte-derived dendritic cells: consequence on the polarization of naive Th cells. J Immunol 170:4943–4952PubMedGoogle Scholar
  53. 53.
    Grimbaldeston MA, Nakae S, Kalesnikoff J et al (2007) Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat Immunol 8:1095–1104PubMedCrossRefGoogle Scholar
  54. 54.
    Kalinski PHC, Snijders A et al (1997) IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2 promote type 2 cytokine production in maturing human naive Th cells. J Immunol 159:28PubMedGoogle Scholar
  55. 55.
    Kitawaki T, Kadowaki N, Sugimoto N, Kambe N, Hori T, Miyachi Y, Nakahata T, Uchiyama T (2006) IgE-activated mast cells in combination with pro-inflammatory factors induce Th2-promoting dendritic cells. Int Immunol 18(12):1789–1799. doi:10.1093/intimm/dxl113 PubMedCrossRefGoogle Scholar
  56. 56.
    McIlroy A, Caron G, Blanchard S, Fremaux I, Duluc D, Delneste Y, Chevailler A, Jeannin P (2006) Histamine and prostaglandin E up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-gamma-induced CXCL10 production by immature human dendritic cells. Immunology 117(4):507–516. doi:10.1111/j.1365-2567.2006.02326.x PubMedCrossRefGoogle Scholar
  57. 57.
    Aoki M, Pawankar R, Niimi Y, Kawana S (2003) Mast cells in basal cell carcinoma express VEGF, IL-8 and RANTES. Int Arch Allergy Immunol 130(3):216–223. doi:10.1159/000069515 PubMedCrossRefGoogle Scholar
  58. 58.
    Wei JJ, Song CW, Sun LC, Yuan Y, Li D, Yan B, Liao SJ, Zhu JH, Wang Q, Zhang GM, Feng ZH (2011) SCF and TLR4 ligand cooperate to augment the tumor-promoting potential of mast cells. Cancer Immunol Immunother. doi:10.1007/s00262-011-1098-z Google Scholar
  59. 59.
    Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP (1998) Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92(11):4150–4166PubMedGoogle Scholar
  60. 60.
    Saito H, Tsujitani S, Ikeguchi M, Maeta M, Kaibara N (1998) Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br J Cancer 78(12):1573–1577PubMedCrossRefGoogle Scholar
  61. 61.
    Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP (1999) Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 5(10):2963–2970PubMedGoogle Scholar
  62. 62.
    Gaudenzio N, Espagnole N, Mars LT, Liblau R, Valitutti S, Espinosa E (2009) Cell-cell cooperation at the T helper cell/mast cell immunological synapse. Blood. doi:10.1182/blood-2009-02-202648 PubMedGoogle Scholar
  63. 63.
    Kambayashi T, Allenspach EJ, Chang JT, Zou T, Shoag JE, Reiner SL, Caton AJ, Koretzky GA (2009) Inducible MHC class II expression by mast cells supports effector and regulatory T cell activation. J Immunol 182(8):4686–4695. doi:10.4049/jimmunol.0803180 PubMedCrossRefGoogle Scholar
  64. 64.
    Aceves SS, Chen D, Newbury RO, Dohil R, Bastian JF, Broide DH (2010) Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-beta1, and increase esophageal smooth muscle contraction. J Allergy Clin Immunol 126(6):1198–1204. doi:10.1016/j.jaci.2010.08.050 PubMedCrossRefGoogle Scholar
  65. 65.
    Wan YY, Flavell RA (2008) TGF-beta and regulatory T cell in immunity and autoimmunity. J Clin Immunol 28(6):647–659. doi:10.1007/s10875-008-9251-y PubMedCrossRefGoogle Scholar
  66. 66.
    Blatner NR, Bonertz A, Beckhove P, Cheon EC, Krantz SB, Strouch M, Weitz J, Koch M, Halverson AL, Bentrem DJ, Khazaie K (2010) In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proc Natl Acad Sci USA 107(14):6430–6435. doi:10.1073/pnas.0913683107 PubMedCrossRefGoogle Scholar
  67. 67.
    Khazaie K, Blatner NR, Khan MW, Gounari F, Gounaris E, Dennis K, Bonertz A, Tsai FN, Strouch MJ, Cheon E, Phillips JD, Beckhove P, Bentrem DJ (2011) The significant role of mast cells in cancer. Cancer Metastasis Rev 30(1):45–60. doi:10.1007/s10555-011-9286-z PubMedCrossRefGoogle Scholar
  68. 68.
    Scholten J, Hartmann K, Gerbaulet A et al (2008) Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgenic Res 17(2):307–315PubMedCrossRefGoogle Scholar
  69. 69.
    Dudeck A, Dudeck J, Scholten J, Petzold A, Surianarayanan S, Kohler A, Peschke K, Vohringer D, Waskow C, Krieg T, Muller W, Waisman A, Hartmann K, Gunzer M, Roers A (2011) Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 34(6):973–984. doi:10.1016/j.immuni.2011.03.028 PubMedCrossRefGoogle Scholar
  70. 70.
    Musch W, Wege AK, Mannel DN et al (2008) Generation and characterization of alpha-chymase-Cre transgenic mice. Genesis 46:163–166PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyDartmouth Medical SchoolLebanonUSA
  2. 2.Norris Cotton Cancer CenterLebanonUSA
  3. 3.King’s College London, King’s Health Partners, Medical Research Council (MRC) Centre for TransplantationGuy’s HospitalLondonUK

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