Skip to main content

Advertisement

SpringerLink
Log in

Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma

  • Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive, primary pleural malignancy with poor prognosis, hypothesized to originate from a chronic inflammatory state within the pleura. Similar to what has been observed in other solid tumors (melanoma, ovarian and colorectal cancer), clinical and pre-clinical MPM investigations have correlated anti-tumor immune responses with improved survival. As such, a better understanding of the complex MPM tumor microenvironment is imperative in strategizing successful immunotherapies. Herein, we review the immune responses vital to the development and progression of MPM, as well as assess the role of immunomodulatory therapies, highlighting recent pre-clinical and clinical immunotherapy investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE, Flores R, Friedberg JS, Pisters K, Monberg M, Obasaju CK, Vogelzang NJ (2009) Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 27:3007–3013

    Article  PubMed  CAS  Google Scholar 

  2. Flores RM, Krug LM, Rosenzweig KE, Venkatraman E, Vincent A, Heelan R, Akhurst T, Rusch VW (2006) Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial. J Thorac Oncol 1:289–295

    Article  PubMed  Google Scholar 

  3. Anraku M, Cunningham KS, Yun Z, Tsao M-S, Zhang L, Keshavjee S, Johnston MR, de Perrot M (2008) Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg 135:823–829

    Article  PubMed  Google Scholar 

  4. Yamada N, Oizumi S, Kikuchi E, Shinagawa N, Konishi-Sakakibara J, Ishimine A, Aoe K, Gemba K, Kishimoto T, Torigoe T, Nishimura M (2010) CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother 59:1543–1549

    Article  PubMed  CAS  Google Scholar 

  5. Hegmans JP, Hemmes A, Hammad H, Boon L, Hoogsteden HC, Lambrecht BN (2006) Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. Eur Respir J 27:1086–1095

    Article  PubMed  CAS  Google Scholar 

  6. Davis JM (1979) The histopathology and ultrastructure of pleural mesotheliomas produced in the rat by injections of crocidolite asbestos. Br J Exp Pathol 60:642–652

    PubMed  CAS  Google Scholar 

  7. Moalli PA, MacDonald JL, Goodglick LA, Kane AB (1987) Acute injury and regeneration of the mesothelium in response to asbestos fibers. Am J Pathol 128:426–445

    PubMed  CAS  Google Scholar 

  8. Shin ML, Firminger HI (1973) Acute and chronic effects of intraperitoneal injection of two types of asbestos in rats with a study of the histopathogenesis and ultrastructure of resulting mesotheliomas. Am J Pathol 70:291–313

    PubMed  CAS  Google Scholar 

  9. Wagner JC, Berry G (1969) Mesotheliomas in rats following inoculation with asbestos. Br J Cancer 23:567–581

    Article  PubMed  CAS  Google Scholar 

  10. Mossman BT, Churg A (1998) Mechanisms in the pathogenesis of asbestosis and silicosis. Am J Respir Crit Care Med 157:1666–1680

    PubMed  CAS  Google Scholar 

  11. Hansen K, Mossman BT (1987) Generation of superoxide (O2 −·) from alveolar macrophages exposed to asbestiform and nonfibrous particles. Cancer Res 47:1681–1686

    PubMed  CAS  Google Scholar 

  12. Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674–677

    Article  PubMed  CAS  Google Scholar 

  13. Tanaka S, Choe N, Hemenway DR, Zhu S, Matalon S, Kagan E (1998) Asbestos inhalation induces reactive nitrogen species and nitrotyrosine formation in the lungs and pleura of the rat. J Clin Investig 102:445–454

    Article  PubMed  CAS  Google Scholar 

  14. Choe N, Tanaka S, Xia W, Hemenway DR, Roggli VL, Kagan E (1997) Pleural macrophage recruitment and activation in asbestos-induced pleural injury. Environ Health Perspect 105 Suppl 5:1257–1260

    PubMed  CAS  Google Scholar 

  15. Wang Y, Faux SP, Hallden G, Kirn DH, Houghton CE, Lemoine NR, Patrick G (2004) Interleukin-1beta and tumour necrosis factor-alpha promote the transformation of human immortalised mesothelial cells by erionite. Int J Oncol 25:173–178

    PubMed  CAS  Google Scholar 

  16. Donaldson K, Murphy F, Duffin R, Poland C (2010) Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Part Fibre Toxicol 7:5

    Article  PubMed  CAS  Google Scholar 

  17. Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WAH, Seaton A, Stone V, Brown S, MacNee W, Donaldson K (2008) Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nano 3:423–428

    Article  CAS  Google Scholar 

  18. Takagi A, Hirose A, Nishimura T, Fukumori N, Ogata A, Ohashi N, Kitajima S, Kanno J (2008) Induction of mesothelioma in p53 +/− mouse by intraperitoneal application of multi-wall carbon nanotube. J Toxicol Sci 33:105–116

    Article  PubMed  CAS  Google Scholar 

  19. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666

    Article  PubMed  CAS  Google Scholar 

  20. 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 348:203–213

    Article  PubMed  CAS  Google Scholar 

  21. Suzuki K, Kadota K, Sima CS, Sadelain M, Rusch VW, Travis WD, Adusumilli PS (2011) Chronic inflammation in tumor stroma is an independent predictor of prolonged survival in epithelioid malignant pleural mesothelioma patients. Cancer Immunol Immunother, Jul 19 [Epub ahead of print]

  22. Amini RM, Aaltonen K, Nevanlinna H, Carvalho R, Salonen L, Heikkila P, Blomqvist C (2007) Mast cells and eosinophils in invasive breast carcinoma. BMC Cancer 7:165

    Article  PubMed  CAS  Google Scholar 

  23. Chan JK, Magistris A, Loizzi V, Lin F, Rutgers J, Osann K, DiSaia PJ, Samoszuk M (2005) Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer. Gynecol Oncol 99:20–25

    Article  PubMed  CAS  Google Scholar 

  24. Ibaraki T, Muramatsu M, Takai S, Jin D, Maruyama H, Orino T, Katsumata T, Miyazaki M (2005) The relationship of tryptase- and chymase-positive mast cells to angiogenesis in stage I non-small cell lung cancer. Eur J Cardiothorac Surg 28:617–621

    Article  PubMed  Google Scholar 

  25. Rajput AB, Turbin DA, Cheang MC, Voduc DK, Leung S, Gelmon KA, Gilks CB, Huntsman DG (2008) Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4, 444 cases. Breast Cancer Res Treat 107:249–257

    Article  PubMed  Google Scholar 

  26. 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 23:8959–8967

    Article  PubMed  Google Scholar 

  27. Cho H, Hur HW, Kim SW, Kim SH, Kim JH, Kim YT, Lee K (2009) Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother 58:15–23

    Article  PubMed  CAS  Google Scholar 

  28. Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E (2009) Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg 137:425–428

    Article  PubMed  Google Scholar 

  29. Kao SC, Pavlakis N, Harvie R, Vardy JL, Boyer MJ, van Zandwijk N, Clarke SJ (2010) High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res 16:5805–5813

    Article  PubMed  CAS  Google Scholar 

  30. Robinson BW, Robinson C, Lake RA (2001) Localised spontaneous regression in mesothelioma–possible immunological mechanism. Lung Cancer 32:197–201

    Article  PubMed  CAS  Google Scholar 

  31. Sakaguchi S, Toda M, Asano M, Itoh M, Morse SS, Sakaguchi N (1996) T cell-mediated maintenance of natural self-tolerance: its breakdown as a possible cause of various autoimmune diseases. J Autoimmun 9:211–220

    Article  PubMed  CAS  Google Scholar 

  32. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH (2001) Regulatory CD4+ CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61:4766–4772

    PubMed  CAS  Google Scholar 

  33. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  PubMed  CAS  Google Scholar 

  34. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A (2003) CD4+ CD25+ regulatory T cells in patients with gastrointestinal malignancies. Cancer 98:1089–1099

    Article  PubMed  Google Scholar 

  35. Gao Q, Qiu S-J, Fan J, Zhou J, Wang X-Y, Xiao Y-S, Xu Y, Li Y-W, Tang Z-Y (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593

    Article  PubMed  Google Scholar 

  36. Rudge G, Barrett SP, Scott B, van Driel IR (2007) Infiltration of a mesothelioma by IFN-gamma-producing cells and tumor rejection after depletion of regulatory T cells. J Immunol 178:4089–4096

    PubMed  CAS  Google Scholar 

  37. Needham DJ, Lee JX, Beilharz MW (2006) Intra-tumoural regulatory T cells: a potential new target in cancer immunotherapy. Biochem Biophys Res Commun 343:684–691

    Article  PubMed  CAS  Google Scholar 

  38. Anraku M, Tagawa T, Wu L, Yun Z, Keshavjee S, Zhang L, Johnston MR, de Perrot M (2010) Synergistic antitumor effects of regulatory T cell blockade combined with pemetrexed in murine malignant mesothelioma. J Immunol 185:956–966

    Article  PubMed  CAS  Google Scholar 

  39. van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, Nowak AK, Lake RA (2009) Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother 58:1219–1228

    Article  PubMed  CAS  Google Scholar 

  40. van der Most RG, Currie AJ, Cleaver AL, Salmons J, Nowak AK, Mahendran S, Larma I, Prosser A, Robinson BW, Smyth MJ, Scalzo AA, Degli-Esposti MA, Lake RA (2009) Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth. PLoS One 4:e6982

    Article  PubMed  CAS  Google Scholar 

  41. Wu L, Yun Z, Tagawa T, Rey-McIntyre K, Anraku M, de Perrot M (2011) Tumor cell repopulation between cycles of chemotherapy is inhibited by regulatory T-cell depletion in a murine mesothelioma model. J Thorac Oncol (Publish Ahead of Print)

  42. Jackaman C, Cornwall S, Lew AM, Zhan Y, Robinson BW, Nelson DJ (2009) Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells. Eur Respir J 34:162–175

    Article  PubMed  CAS  Google Scholar 

  43. Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18:349–355

    Article  PubMed  CAS  Google Scholar 

  44. Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196:254–265

    Article  PubMed  CAS  Google Scholar 

  45. Koukourakis MI, Giatromanolaki A, Kakolyris S, O’Byrne KJ, Apostolikas N, Skarlatos J, Gatter KC, Harris AL (1998) Different patterns of stromal and cancer cell thymidine phosphorylase reactivity in non-small-cell lung cancer: impact on tumour neoangiogenesis and survival. Br J Cancer 77:1696–1703

    Article  PubMed  CAS  Google Scholar 

  46. Lissbrant IF, Stattin P, Wikstrom P, Damber JE, Egevad L, Bergh A (2000) Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int J Oncol 17:445–451

    PubMed  CAS  Google Scholar 

  47. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78

    Article  PubMed  CAS  Google Scholar 

  48. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51

    Article  PubMed  CAS  Google Scholar 

  49. Salvesen HB, Akslen LA (1999) Significance of tumour-associated macrophages, vascular endothelial growth factor and thrombospondin-1 expression for tumour angiogenesis and prognosis in endometrial carcinomas. Int J Cancer 84:538–543

    Article  PubMed  CAS  Google Scholar 

  50. Volodko N, Reiner A, Rudas M, Jakesz R (1998) Tumour-associated macrophages in breast cancer and their prognostic correlations. The Breast 7:99–105

    Article  Google Scholar 

  51. Izzi V, Chiurchiu V, D’Aquilio F, Palumbo C, Tresoldi I, Modesti A, Baldini PM (2009) Differential effects of malignant mesothelioma cells on THP-1 monocytes and macrophages. Int J Oncol 34:543–550

    PubMed  CAS  Google Scholar 

  52. Baratelli F, Lin Y, Zhu L, Yang SC, Heuze-Vourc’h N, Zeng G, Reckamp K, Dohadwala M, Sharma S, Dubinett SM (2005) Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 175:1483–1490

    PubMed  CAS  Google Scholar 

  53. Sharma S, Yang S-C, Zhu L, Reckamp K, Gardner B, Baratelli F, Huang M, Batra RK, Dubinett SM (2005) Tumor Cyclooxygenase-2/Prostaglandin E2–dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 65:5211–5220

    Article  PubMed  CAS  Google Scholar 

  54. Miselis NR, Wu ZJ, Van Rooijen N, Kane AB (2008) Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma. Mol Cancer Ther 7:788–799

    Article  PubMed  CAS  Google Scholar 

  55. Steinman RM (2008) Dendritic cells in vivo: a key target for a new vaccine science. Immunity 29:319–324

    Article  PubMed  CAS  Google Scholar 

  56. Steinman RM, Banchereau J (2007) Taking dendritic cells into medicine. Nature 449:419–426

    Article  PubMed  CAS  Google Scholar 

  57. Hegmans JP, Hemmes A, Aerts JG, Hoogsteden HC, Lambrecht BN (2005) Immunotherapy of murine malignant mesothelioma using tumor lysate-pulsed dendritic cells. Am J Respir Crit Care Med 171:1168–1177

    Article  PubMed  Google Scholar 

  58. Veltman JD, Lambers ME, van Nimwegen M, de Jong S, Hendriks RW, Hoogsteden HC, Aerts JG, Hegmans JP (2010) Low-dose cyclophosphamide synergizes with dendritic cell-based immunotherapy in antitumor activity. J Biomed Biotechnol 2010:798467

    Article  PubMed  CAS  Google Scholar 

  59. Wada S, Yoshimura K, Hipkiss EL, Harris TJ, Yen H-R, Goldberg MV, Grosso JF, Getnet D, Demarzo AM, Netto GJ, Anders R, Pardoll DM, Drake CG (2009) Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model. Cancer Res 69:4309–4318

    Article  PubMed  CAS  Google Scholar 

  60. Ho M, Hassan R, Zhang J, Wang QC, Onda M, Bera T, Pastan I (2005) Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients. Clin Cancer Res 11:3814–3820

    Article  PubMed  CAS  Google Scholar 

  61. Johnston FM, Tan MC, Tan BR Jr, Porembka MR, Brunt EM, Linehan DC, Simon PO Jr, Plambeck-Suess S, Eberlein TJ, Hellstrom KE, Hellstrom I, Hawkins WG, Goedegebuure P (2009) Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer. Clin Cancer Res 15:6511–6518

    Article  PubMed  CAS  Google Scholar 

  62. Keilholz U, Letsch A, Busse A, Asemissen AM, Bauer S, Blau IW, Hofmann WK, Uharek L, Thiel E, Scheibenbogen C (2009) A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood 113:6541–6548

    Article  PubMed  CAS  Google Scholar 

  63. May RJ, Dao T, Pinilla-Ibarz J, Korontsvit T, Zakhaleva V, Zhang RH, Maslak P, Scheinberg DA (2007) Peptide epitopes from the Wilms’ tumor 1 oncoprotein stimulate CD4+ and CD8+ T cells that recognize and kill human malignant mesothelioma tumor cells. Clin Cancer Res 13:4547–4555

    Article  PubMed  CAS  Google Scholar 

  64. Rezvani K, Brenchley JM, Price DA, Kilical Y, Gostick E, Sewell AK, Li J, Mielke S, Douek DC, Barrett AJ (2005) T-cell responses directed against multiple HLA-A*0201-restricted epitopes derived from Wilms’ tumor 1 protein in patients with leukemia and healthy donors: identification, quantification, and characterization. Clin Cancer Res 11:8799–8807

    Article  PubMed  CAS  Google Scholar 

  65. Hassan R, Ho M (2008) Mesothelin targeted cancer immunotherapy. Eur J Cancer 44:46–53

    Article  PubMed  CAS  Google Scholar 

  66. Wheatley-Price P, Yang B, Patsios D, Patel D, Ma C, Xu W, Leighl N, Feld R, Cho BCJ, O’Sullivan B, Roberts H, Tsao MS, Tammemagi M, Anraku M, Chen Z, de Perrot M, Liu G (2010) Soluble mesothelin-related peptide and osteopontin as markers of response in malignant mesothelioma. J Clin Oncol 28:3316–3322

    Article  PubMed  Google Scholar 

  67. Robinson BWS, Creaney J, Lake R, Nowak A, Musk AW, de Klerk N, Winzell P, Hellstrom KE, Hellstrom I (2003) Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 362:1612–1616

    Article  PubMed  CAS  Google Scholar 

  68. Hassan R, Williams-Gould J, Steinberg SM, Liewehr DJ, Yokokawa J, Tsang KY, Surawski RJ, Scott T, Camphausen K (2006) Tumor-directed radiation and the immunotoxin SS1P in the treatment of mesothelin-expressing tumor xenografts. Clin Cancer Res 12:4983–4988

    Article  PubMed  CAS  Google Scholar 

  69. Zhang Y, Xiang L, Hassan R, Paik CH, Carrasquillo JA, Jang BS, Le N, Ho M, Pastan I (2006) Synergistic antitumor activity of taxol and immunotoxin SS1P in tumor-bearing mice. Clin Cancer Res 12:4695–4701

    Article  PubMed  CAS  Google Scholar 

  70. Hassan R, Ebel W, Routhier EL, Patel R, Kline JB, Zhang J, Chao Q, Jacob S, Turchin H, Gibbs L, Phillips MD, Mudali S, Iacobuzio-Donahue C, Jaffee EM, Moreno M, Pastan I, Sass PM, Nicolaides NC, Grasso L (2007) Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin. Cancer Immun 7:20

    PubMed  Google Scholar 

  71. Sadelain M, Rivière I, Brentjens R (2003) Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer 3:35–45

    Article  PubMed  CAS  Google Scholar 

  72. Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, Varela-Rohena A, Haines KM, Heitjan DF, Albelda SM, Carroll RG, Riley JL, Pastan I, June CH (2009) Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA 106:3360–3365

    Article  PubMed  CAS  Google Scholar 

  73. Moon EK, Carpenito C, Sun J, Wang L-CS, Kapoor V, Predina JD, Powell DJ, Riley J, June CH, Albelda SM (2011) Expression of a functional CCR2 receptor enhances tumor localization and eradication by human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin Cancer Res 17(14):4719–4730

    Google Scholar 

  74. Huber JP, David Farrar J (2011) Regulation of effector and memory T-cell functions by type I interferon. Immunology 132:466–474

    Article  PubMed  CAS  Google Scholar 

  75. Odaka M, Sterman DH, Wiewrodt R, Zhang Y, Kiefer M, Amin KM, Gao G-P, Wilson JM, Barsoum J, Kaiser LR, Albelda SM (2001) Eradication of intraperitoneal and distant tumor by adenovirus-mediated interferon-β Gene therapy is attributable to induction of systemic immunity. Cancer Res 61:6201–6212

    PubMed  CAS  Google Scholar 

  76. Kruklitis RJ, Singhal S, Delong P, Kapoor V, Sterman DH, Kaiser LR, Albelda SM (2004) Immuno-gene therapy with interferon-beta before surgical debulking delays recurrence and improves survival in a murine model of malignant mesothelioma. J Thorac Cardiovasc Surg 127:123–130

    Article  PubMed  CAS  Google Scholar 

  77. Smith KA (1988) Interleukin-2: inception, impact, and implications. Science 240:1169–1176

    Article  PubMed  CAS  Google Scholar 

  78. Kern DE, Gillis S, Okada M, Henney CS (1981) The role of interleukin-2 (IL-2) in the differentiation of cytotoxic T cells: the effect of monoclonal anti-IL-2 antibody and absorption with IL-2 dependent T cell lines. J Immunol 127:1323–1328

    PubMed  CAS  Google Scholar 

  79. Jackaman C, Bundell CS, Kinnear BF, Smith AM, Filion P, van Hagen D, Robinson BW, Nelson DJ (2003) IL-2 intratumoral immunotherapy enhances CD8+ T cells that mediate destruction of tumor cells and tumor-associated vasculature: a novel mechanism for IL-2. J Immunol 171:5051–5063

    PubMed  CAS  Google Scholar 

  80. Jackaman C, Lew AM, Zhan Y, Allan JE, Koloska B, Graham PT, Robinson BW, Nelson DJ (2008) Deliberately provoking local inflammation drives tumors to become their own protective vaccine site. Int Immunol 20:1467–1479

    Article  PubMed  CAS  Google Scholar 

  81. van Mierlo GJ, den Boer AT, Medema JP, van der Voort EI, Fransen MF, Offringa R, Melief CJ, Toes RE (2002) CD40 stimulation leads to effective therapy of CD40(-) tumors through induction of strong systemic cytotoxic T lymphocyte immunity. Proc Natl Acad Sci USA 99:5561–5566

    Article  PubMed  CAS  Google Scholar 

  82. Del Vecchio M, Bajetta E, Canova S, Lotze MT, Wesa A, Parmiani G, Anichini A (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13:4677–4685

    Article  PubMed  CAS  Google Scholar 

  83. Brunda MJ, Luistro L, Warrier RR, Wright RB, Hubbard BR, Murphy M, Wolf SF, Gately MK (1993) Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med 178:1223–1230

    Article  PubMed  CAS  Google Scholar 

  84. Zou JP, Yamamoto N, Fujii T, Takenaka H, Kobayashi M, Herrmann SH, Wolf SF, Fujiwara H, Hamaoka T (1995) Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T cells. Int Immunol 7:1135–1145

    Article  PubMed  CAS  Google Scholar 

  85. Caminschi I, Venetsanakos E, Leong CC, Garlepp MJ, Scott B, Robinson BW (1998) Interleukin-12 induces an effective antitumor response in malignant mesothelioma. Am J Respir Cell Mol Biol 19:738–746

    PubMed  CAS  Google Scholar 

  86. Caminschi I, Venetsanakos E, Leong CC, Garlepp MJ, Robinson BW, Scott B (1999) Cytokine gene therapy of mesothelioma. Immune and antitumor effects of transfected interleukin-12. Am J Respir Cell Mol Biol 21:347–356

    PubMed  CAS  Google Scholar 

  87. Fridlender ZG, Buchlis G, Kapoor V, Cheng G, Sun J, Singhal S, Crisanti MC, Wang LC, Heitjan D, Snyder LA, Albelda SM (2010) CCL2 blockade augments cancer immunotherapy. Cancer Res 70:109–118

    Article  PubMed  CAS  Google Scholar 

  88. Kim S, Buchlis G, Fridlender ZG, Sun J, Kapoor V, Cheng G, Haas A, Cheung HK, Zhang X, Corbley M, Kaiser LR, Ling L, Albelda SM (2008) Systemic blockade of transforming growth factor-beta signaling augments the efficacy of immunogene therapy. Cancer Res 68:10247–10256

    Article  PubMed  CAS  Google Scholar 

  89. Marie JC, Letterio JJ, Gavin M, Rudensky AY (2005) TGF-β1 maintains suppressor function and Foxp3 expression in CD4+ CD25+ regulatory T cells. J Exp Med 201:1061–1067

    Article  PubMed  CAS  Google Scholar 

  90. Thomas DA, Massagué J (2005) TGF-[beta] directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8:369–380

    Article  PubMed  CAS  Google Scholar 

  91. Ahmadzadeh M, Rosenberg SA (2005) TGF-β1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol 174:5215–5223

    PubMed  CAS  Google Scholar 

  92. Allavena P, Sica A, Garlanda C, Mantovani A (2008) The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev 222:155–161

    Article  PubMed  CAS  Google Scholar 

  93. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16:183–194

    Article  PubMed  CAS  Google Scholar 

  94. Rodriguez PC, Ochoa AC (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 222:180–191

    Article  PubMed  CAS  Google Scholar 

  95. Currie AJ, van der Most RG, Broomfield SA, Prosser AC, Tovey MG, Robinson BW (2008) Targeting the effector site with IFN-alphabeta-inducing TLR ligands reactivates tumor-resident CD8 T cell responses to eradicate established solid tumors. J Immunol 180:1535–1544

    PubMed  CAS  Google Scholar 

  96. Broomfield SA, van der Most RG, Prosser AC, Mahendran S, Tovey MG, Smyth MJ, Robinson BW, Currie AJ (2009) Locally administered TLR7 agonists drive systemic antitumor immune responses that are enhanced by anti-CD40 immunotherapy. J Immunol 182:5217–5224

    Article  PubMed  CAS  Google Scholar 

  97. Egen JG, Kuhns MS, Allison JP (2002) CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 3:611–618

    Article  PubMed  CAS  Google Scholar 

  98. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736

    Article  PubMed  CAS  Google Scholar 

  99. Shrikant P, Khoruts A, Mescher MF (1999) CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. Immunity 11:483–493

    Article  PubMed  CAS  Google Scholar 

  100. van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 190:355–366

    Article  PubMed  Google Scholar 

  101. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  PubMed  CAS  Google Scholar 

  102. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr., Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526

    Google Scholar 

  103. Adusumilli PS, Eisenberg DP, Stiles BM, Chung S, Chan M-K, Rusch VW, Fong Y (2006) Intraoperative localization of lymph node metastases with a replication-competent herpes simplex virus. J Thorac Cardiovasc Surg 132:1179.e1–1188.e1

    Article  Google Scholar 

  104. Adusumilli PS, Stiles BM, Chan M-K, Mullerad M, Eisenberg DP, Ben-Porat L, Huq R, Rusch VW, Fong Y (2006) Imaging and therapy of malignant pleural mesothelioma using replication-competent herpes simplex viruses. J Gene Med 8:603–615

    Article  PubMed  CAS  Google Scholar 

  105. Adusumilli PS, Stiles BM, Chan MK, Eisenberg DP, Yu Z, Stanziale SF, Huq R, Wong RJ, Rusch VW, Fong Y (2006) Real-time diagnostic imaging of tumors and metastases by use of a replication-competent herpes vector to facilitate minimally invasive oncological surgery. FASEB J 20:726–728

    PubMed  CAS  Google Scholar 

  106. Sterman DH, Recio A, Carroll RG, Gillespie CT, Haas A, Vachani A, Kapoor V, Sun J, Hodinka R, Brown JL, Corbley MJ, Parr M, Ho M, Pastan I, Machuzak M, Benedict W, Zhang XQ, Lord EM, Litzky LA, Heitjan DF, June CH, Kaiser LR, Vonderheide RH, Albelda SM, Kanther M (2007) A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses. Clin Cancer Res 13:4456–4466

    Article  PubMed  CAS  Google Scholar 

  107. Sterman DH, Recio A, Haas AR, Vachani A, Katz SI, Gillespie CT, Cheng G, Sun J, Moon E, Pereira L, Wang X, Heitjan DF, Litzky L, June CH, Vonderheide RH, Carroll RG, Albelda SM (2010) A phase I trial of repeated intrapleural adenoviral-mediated interferon-beta gene transfer for mesothelioma and metastatic pleural effusions. Mol Ther 18:852–860

    Article  PubMed  CAS  Google Scholar 

  108. Boutin C, Nussbaum E, Monnet I, Bignon J, Vanderschueren R, Guerin JC, Menard O, Mignot P, Dabouis G, Douillard JY (1994) Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer 74:2460–2467

    Article  PubMed  CAS  Google Scholar 

  109. Goey SH, Eggermont AM, Punt CJ, Slingerland R, Gratama JW, Oosterom R, Oskam R, Bolhuis RL, Stoter G (1995) Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study. Br J Cancer 72:1283–1288

    Article  PubMed  CAS  Google Scholar 

  110. Astoul P, Picat-Joossen D, Viallat JR, Boutin C (1998) Intrapleural administration of interleukin-2 for the treatment of patients with malignant pleural mesothelioma: a phase II study. Cancer 83:2099–2104

    Article  PubMed  CAS  Google Scholar 

  111. Castagneto B, Zai S, Mutti L, Lazzaro A, Ridolfi R, Piccolini E, Ardizzoni A, Fumagalli L, Valsuani G, Botta M (2001) Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: results of a phase II study on 31 consecutive patients. Lung Cancer 31:303–310

    Article  PubMed  CAS  Google Scholar 

  112. Lucchi M, Chella A, Melfi F, Dini P, Tibaldi C, Fontanini G, Mussi A (2007) Four-modality therapy in malignant pleural mesothelioma: a phase II study. J Thorac Oncol 2:237–242

    Article  PubMed  Google Scholar 

  113. Lucchi M, Chella A, Melfi F, Dini P, Ambrogi M, Fino L, Fontanini G, Mussi A (2007) A phase II study of intrapleural immuno-chemotherapy, pleurectomy/decortication, radiotherapy, systemic chemotherapy and long-term sub-cutaneous IL-2 in stage II-III malignant pleural mesothelioma. Eur J Cardiothorac Surg 31:529–533 discussion 533-4

    Article  PubMed  Google Scholar 

  114. Bretti S, Berruti A, Dogliotti L, Castagneto B, Bertulli R, Spadaro P, Toscano G, Astorre P, Verusio C, Lionetto R, Bruzzi P, Santoro A (1998) Combined epirubicin and interleukin-2 regimen in the treatment of malignant mesothelioma: a multicenter phase II study of the Italian group on rare tumors. Tumori 84:558–561

    PubMed  CAS  Google Scholar 

  115. Mulatero CW, Penson RT, Papamichael D, Gower NH, Evans M, Rudd RM (2001) A phase II study of combined intravenous and subcutaneous interleukin-2 in malignant pleural mesothelioma. Lung Cancer 31:67–72

    Article  PubMed  CAS  Google Scholar 

  116. Ali G, Boldrini L, Lucchi M, Picchi A, Dell’Omodarme M, Prati MC, Mussi A, Corsi V, Fontanini G (2009) Treatment with interleukin-2 in malignant pleural mesothelioma: immunological and angiogenetic assessment and prognostic impact. Br J Cancer 101:1869–1875

    Article  PubMed  CAS  Google Scholar 

  117. Ali G, Boldrini L, Lucchi M, Mussi A, Corsi V, Fontanini G (2009) Tryptase mast cells in malignant pleural mesothelioma as an independent favorable prognostic factor. J Thorac Oncol 4:348–354

    Article  PubMed  Google Scholar 

  118. Hegmans JP, Veltman JD, Lambers ME, de Vries IJ, Figdor CG, Hendriks RW, Hoogsteden HC, Lambrecht BN, Aerts JG (2010) Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. Am J Respir Crit Care Med 181:1383–1390

    Article  PubMed  CAS  Google Scholar 

  119. Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, Mellman I, Prindiville SA, Viner JL, Weiner LM, Matrisian LM (2009) The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res 15:5323–5337

    Article  PubMed  Google Scholar 

  120. Xue SA, Gao L, Thomas S, Hart DP, Xue JZ, Gillmore R, Voss RH, Morris E, Stauss HJ (2010) Development of a Wilms’ tumor antigen-specific T-cell receptor for clinical trials: engineered patient’s T cells can eliminate autologous leukemia blasts in NOD/SCID mice. Haematologica 95:126–134

    Article  PubMed  CAS  Google Scholar 

  121. Amin KM, Litzky LA, Smythe WR, Mooney AM, Morris JM, Mews DJ, Pass HI, Kari C, Rodeck U, Rauscher FJ III et al (1995) Wilms’ tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma. Am J Pathol 146:344–356

    PubMed  CAS  Google Scholar 

  122. Oates J, Edwards C (2000) HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma. Histopathology 36:341–347

    Article  PubMed  CAS  Google Scholar 

  123. Krug LM, Dao T, Brown AB, Maslak P, Travis W, Bekele S, Korontsvit T, Zakhaleva V, Wolchok J, Yuan J, Li H, Tyson L, Scheinberg DA (2010) WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer. Cancer Immunol Immunother 59:1467–1479

    Article  PubMed  CAS  Google Scholar 

  124. Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I (2007) Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. Infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res 13:5144–5149

    Article  PubMed  CAS  Google Scholar 

  125. Kreitman RJ, Hassan R, FitzGerald DJ, Pastan I (2009) Phase I trial of continuous infusion anti-mesothelin recombinant immunotoxin SS1P. Clin Cancer Res 15:5274–5279

    Article  PubMed  CAS  Google Scholar 

  126. Hassan R, Cohen SJ, Phillips M, Pastan I, Sharon E, Kelly RJ, Schweizer C, Weil S, Laheru D (2010) Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin Cancer Res 16:6132–6138

    Article  PubMed  CAS  Google Scholar 

  127. Pages F, Galon J, Fridman WH (2008) The essential role of the in situ immune reaction in human colorectal cancer. J Leukoc Biol 84:981–987

    Article  PubMed  CAS  Google Scholar 

  128. Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27:5944–5951

    Article  PubMed  CAS  Google Scholar 

  129. 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 313:1960–1964

    Article  PubMed  CAS  Google Scholar 

  130. 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 77:1303–1310

    Article  PubMed  CAS  Google Scholar 

  131. Broomfield SA et al (2005) Partial, but not complete, tumor-debulking surgery promotes protective antitumor memory when combined with chemotherapy and adjuvant immunotherapy. Cancer Res 65(17):7580–7584

    Google Scholar 

Download references

Acknowledgments

This work was supported in part by Mesothelioma Applied Research Foundation (MARF) Grant in memory of Lance S. Ruble, William H. Goodwin and Alice Goodwin, the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center, American Association for Thoracic Surgery (AATS)-Third Edward D. Churchill Research Scholarship, IASLC—International Association for the Study of Lung Cancer Young Investigator Award, National Lung Cancer Partnership/LUNGevity Foundation Research Grant, Stony Wold-Herbert Fund, New York State Empire Clinical Research Investigator Program (ECRIP), U54CA137788/U54CA132378 from the National Cancer Institute, and PR101053 Department of Defense Research Grants.

Conflict of interest

All authors affirm that we have no actual or potential conflict of interest including any financial, personal, or other relationships with other people or organizations.

Author information

Authors and Affiliations

  1. Division of Thoracic Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Adam J. Bograd, Kei Suzuki, Eva Vertes, Christos Colovos, Eduardo A. Morales & Prasad S. Adusumilli

  2. Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Adam J. Bograd, Eva Vertes, Christos Colovos, Michel Sadelain & Prasad S. Adusumilli

Authors
  1. Adam J. Bograd
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kei Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eva Vertes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christos Colovos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eduardo A. Morales
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michel Sadelain
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Prasad S. Adusumilli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Prasad S. Adusumilli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bograd, A.J., Suzuki, K., Vertes, E. et al. Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma. Cancer Immunol Immunother 60, 1509–1527 (2011). https://doi.org/10.1007/s00262-011-1103-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-011-1103-6

Keywords

Search

Navigation