nach oben

Erschienen in:

01.10.2008 | Original Article

Lung cancer patients’ CD4⁺ T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells

verfasst von: Minu K. Srivastava, Jacobus J. Bosch, James A. Thompson, Bruce R. Ksander, Martin J. Edelman, Suzanne Ostrand-Rosenberg

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 10/2008

Einloggen, um Zugang zu erhalten

Abstract

Background

Advanced non-small cell lung cancer (NSCLC) remains an incurable disease. Immunotherapies that activate patients’ T cells against resident tumor cells are being developed; however, these approaches may not be effective in NSCLC patients due to tumor-induced immune suppression. A major cause of immune suppression is myeloid-derived suppressor cells (MDSC). Because of the strategic role of CD4⁺ T lymphocytes in the activation of cytotoxic CD8⁺ T cells and immune memory, we are developing cell-based vaccines that activate tumor-specific CD4⁺ T cells in the presence of MDSC. The vaccines are NSCLC cell lines transfected with costimulatory (CD80) plus major histocompatibility complex class II (MHC II) genes that are syngeneic to the recipient. The absence of invariant chain promotes the presentation of endogenously synthesized tumor antigens, and the activation of MHC II-restricted, tumor-antigen-specific CD4⁺ T cells.

Methods

Potential vaccine efficacy was tested in vitro by priming and boosting peripheral blood mononuclear cells from ten NSCLC patients who had varying levels of MDSC. CD4⁺ T cell activation was quantified by measuring Type 1 and Type 2 cytokine release.

Results

The vaccines activated CD4⁺ T cells from all ten patients, despite the presence of CD33⁺CD11b⁺ MDSC. Activated CD4⁺ T cells were specific for NSCLC and did not cross-react with tumor cells derived from non-lung tissue or normal lung fibroblasts.

Conclusions

The NSCLC vaccines activate tumor-specific CD4⁺ T cells in the presence of potent immune suppression, and may be useful for the treatment of patients with NSCLC.

Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689PubMed

Armstrong TD, Clements VK, Martin BK, Ting JP, Ostrand-Rosenberg S (1997) Major histocompatibility complex class II-transfected tumor cells present endogenous antigen and are potent inducers of tumor-specific immunity. Proc Natl Acad Sci USA 94:6886–6891PubMedCrossRef

Atanackovic D, Altorki NK, Stockert E, Williamson B, Jungbluth AA, Ritter E, Santiago D, Ferrara CA, Matsuo M, Selvakumar A, Dupont B, Chen YT, Hoffman EW, Ritter G, Old LJ, Gnjatic S (2004) Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol 172:3289–3296PubMed

Baskar S, Glimcher L, Nabavi N, Jones RT, Ostrand-Rosenberg S (1995) Major histocompatibility complex class II+B7-1+ tumor cells are potent vaccines for stimulating tumor rejection in tumor-bearing mice. J Exp Med 181:619–629PubMedCrossRef

Bosch JJ, Thompson JA, Srivastava MK, Iheagwara UK, Murray TG, Lotem M, Ksander BR, Ostrand-Rosenberg S (2007) MHC class II-transduced tumor cells originating in the immune-privileged eye prime and boost CD4+ T lymphocytes that cross-react with primary and metastatic uveal melanoma cells. Cancer Res 67:4499–4506PubMedCrossRef

Bronte V, Wang M, Overwijk WW, Surman DR, Pericle F, Rosenberg SA, Restifo NP (1998) Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J Immunol 161:5313–5320PubMed

Butts C, Murray N, Maksymiuk A, Goss G, Marshall E, Soulieres D, Cormier Y, Ellis P, Price A, Sawhney R, Davis M, Mansi J, Smith C, Vergidis D, MacNeil M, Palmer M (2005) Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 23:6674–6681PubMedCrossRef

Danna EA, Sinha P, Gilbert M, Clements VK, Pulaski BA, Ostrand-Rosenberg S (2004) Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Res 64:2205–2211PubMedCrossRef

Dissanayake SK, Thompson JA, Bosch JJ, Clements VK, Chen PW, Ksander BR, Ostrand-Rosenberg S (2004) Activation of tumor-specific CD4(+) T lymphocytes by major histocompatibility complex class II tumor cell vaccines: a novel cell-based immunotherapy. Cancer Res 64:1867–1874PubMedCrossRef

10.

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

11.

Finn OJ (2003) Cancer vaccines: between the idea and the reality. Nat Rev Immunol 3:630–641PubMedCrossRef

12.

Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, Schreiber H (2007) The terminology issue for myeloid-derived suppressor cells. Cancer Res 67:425; author reply 426

13.

Hirschowitz EA, Foody T, Hidalgo GE, Yannelli JR (2007) Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells. Lung Cancer 57:365–372PubMedCrossRef

14.

Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, Divino CM, Chen SH (2006) Gr-1⁺CD115⁺ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 66:1123–1131PubMedCrossRef

15.

Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP (2003) CD4⁺ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421:852–856PubMedCrossRef

16.

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66PubMedCrossRef

17.

Kaufman HLDisis ML (2004) Immune system versus tumor: shifting the balance in favor of DCs and effective immunity. J Clin Invest 113:664–667

18.

Koch N, Wong GH, Schrader JW (1984) Ia antigens and associated invariant chain are induced simultaneously in lines of T-dependent mast cells by recombinant interferon-gamma. J Immunol 132:1361–1369PubMed

19.

Kong F, Jirtle RL, Huang DH, Clough RW, Anscher MS (1999) Plasma transforming growth factor-beta1 level before radiotherapy correlates with long term outcome of patients with lung carcinoma. Cancer 86:1712–1719PubMedCrossRef

20.

Kusmartsev S, Gabrilovich DI (2002) Immature myeloid cells and cancer-associated immune suppression. Cancer Immunol Immunother 51:293–298PubMedCrossRef

21.

Kusmartsev SA, Li Y, Chen SH (2000) Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol 165:779–785PubMed

22.

Letterio JJ, Roberts AB (1998) Regulation of immune responses by TGF-beta. Annu Rev Immunol 16:137–161PubMedCrossRef

23.

Muntasell A, Carrascal M, Alvarez I, Serradell L, van Veelen P, Verreck FA, Koning F, Abian J, Jaraquemada D (2004) Dissection of the HLA-DR4 peptide repertoire in endocrine epithelial cells: strong influence of invariant chain and HLA-DM expression on the nature of ligands. J Immunol 173:1085–1093PubMed

24.

Nemunaitis J (2007) A review of vaccine clinical trials for non-small cell lung cancer. Expert Opin Biol Ther 7:89–102PubMedCrossRef

25.

Nemunaitis J, Dillman RO, Schwarzenberger PO, Senzer N, Cunningham C, Cutler J, Tong A, Kumar P, Pappen B, Hamilton C, DeVol E, Maples PB, Liu L, Chamberlin T, Shawler DL, Fakhrai H (2006) Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 24:4721–4730PubMedCrossRef

26.

Nemunaitis J, Jahan T, Ross H, Sterman D, Richards D, Fox B, Jablons D, Aimi J, Lin A, Hege K (2006) Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX vaccine in advanced-stage non-small-cell lung cancer. Cancer Gene Ther 13:555–562PubMedCrossRef

27.

Nemunaitis J, Sterman D, Jablons D, Smith JW II, Fox B, Maples P, Hamilton S, Borellini F, Lin A, Morali S, Hege K (2004) Granulocyte-macrophage colony-stimulating factor gene-modified autologous tumor vaccines in non-small-cell lung cancer. J Natl Cancer Inst 96:326–331PubMedCrossRef

28.

O’Mahony D, Kummar S, Gutierrez ME (2005) Non-small-cell lung cancer vaccine therapy: a concise review. J Clin Oncol 23:9022–9028PubMedCrossRef

29.

Pulaski BA, Ostrand-Rosenberg S (1998) Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Cancer Res 58:1486–1493PubMed

30.

Raez LE, Cassileth PA, Schlesselman JJ, Padmanabhan S, Fisher EZ, Baldie PA, Sridhar K, Podack ER (2003) Induction of CD8 T-cell-Ifn-gamma response and positive clinical outcome after immunization with gene-modified allogeneic tumor cells in advanced non-small-cell lung carcinoma. Cancer Gene Ther 10:850–858PubMedCrossRef

31.

Raez LE, Cassileth PA, Schlesselman JJ, Sridhar K, Padmanabhan S, Fisher EZ, Baldie PA, Podack ER (2004) Allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced non-small-cell lung cancer. J Clin Oncol 22:2800–2807PubMedCrossRef

32.

Raez LE, Rosenblatt JD, Podack ER (2006) Present and future of lung cancer vaccines. Expert Opin Emerg Drugs 11:445–459PubMedCrossRef

33.

Ramos TC, Vinageras EN, Ferrer MC, Verdecia BG, Rupale IL, Perez LM, Marinello GG, Rodriguez RP, Davila AL (2006) Treatment of NSCLC patients with an EGF-based cancer vaccine: report of a Phase I trial. Cancer Biol Ther 5:145–149PubMedCrossRef

34.

Serafini P, De Santo C, Marigo I, Cingarlini S, Dolcetti L, Gallina G, Zanovello P, Bronte V (2004) Derangement of immune responses by myeloid suppressor cells. Cancer Immunol Immunother 53:64–72PubMedCrossRef

35.

Shedlock DJ, Shen H (2003) Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300:337–339PubMedCrossRef

36.

Shepherd FA (2000) Chemotherapy for advanced non-small-cell lung cancer: modest progress, many choices. J Clin Oncol 18:35S–38SPubMed

37.

Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218PubMed

38.

Sinha P, Clements V, Bunt SK, Albelda SM, Ostrand-Rosenberg (2007) Cross-talk between myeloid-derived suppressor cells and macorphages subverts tumor immunity towards a type 2 response. J Immunol 179:977–983PubMed

39.

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

40.

Steimle V, Siegrist CA, Mottet A, Lisowska-Grospierre B, Mach B (1994) Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science 265:106–109PubMedCrossRef

41.

Strober S (1984) Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships. Annu Rev Immunol 2:219–237PubMedCrossRef

42.

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

43.

Terabe M, Matsui S, Park JM, Mamura M, Noben-Trauth N, Donaldson DD, Chen W, Wahl SM, Ledbetter S, Pratt B, Letterio JJ, Paul WE, Berzofsky JA (2003) Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 198:1741–1752PubMedCrossRef

44.

Thompson JA, Dissanayake SK, Ksander BR, Knutson KL, Disis ML, Ostrand-Rosenberg S (2006) Tumor cells transduced with the MHC class II Transactivator and CD80 activate tumor-specific CD4+ T cells whether or not they are silenced for invariant chain. Cancer Res 66:1147–1154PubMedCrossRef

45.

Thompson JA, Srivastava MK, Bosch JJ, Clements V, Ksander BR, Ostrand-Rosenberg S (2007) The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor-reactive type 1 CD4+ T lymphocytes. Cancer Immunol Immunother 57:389–398PubMedCrossRef

46.

Young MR, Lathers DM (1999) Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int J Immunopharmacol 21:241–252PubMedCrossRef

47.

Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O’Neill A, Mier J, Ochoa AC (2005) Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65:3044–3048PubMed

Titel: Lung cancer patients’ CD4+ T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells
verfasst von: Minu K. Srivastava
Jacobus J. Bosch
James A. Thompson
Bruce R. Ksander
Martin J. Edelman
Suzanne Ostrand-Rosenberg
Publikationsdatum: 01.10.2008
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 10/2008
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-008-0490-9

Neu im Fachgebiet Onkologie

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Springer Medizin

Lung cancer patients’ CD4⁺ T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells