Skip to main content

Advertisement

SpringerLink
Log in

CTLA-4 blockade augments human T lymphocyte-mediated suppression of lung tumor xenografts in SCID mice

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

Abstract

Previous studies by others using transplantable murine tumor models have demonstrated that the administration of antibodies that block CTLA-4 interaction with B7 can provoke the elimination of established tumors, and that the tumor suppression is mediated by T-cells and/or cells expressing NK1.1. Studies from our lab have established in a human/severe combined immunodeficient (SCID) mouse chimeric model that autologous peripheral blood leukocytes (PBL) can suppress the growth of tumor xenografts in a PBL dose-dependent fashion, and that this suppression is dependent upon the patient’s T and NK cells. Using this human/mouse chimeric model, we sought to determine whether an antibody blockade of CTLA-4 would enhance the anti-tumor response of a patient’s PBL. It was first important to determine whether the tumor suppression observed in the SCID model was dependent upon CD28/B7 co-stimulation. Blockade of B7 with a human CTLA-4-Ig fusion protein completely abrogated the lymphocyte-mediated tumor suppression, confirming in this model that tumor suppression is dependent upon a CD28/B7 co-stimulation. Using two different CTLA-4 specific monoclonal antibodies, we observed that CTLA-4 blockade significantly enhanced the human lymphocyte-mediated tumor suppression in mice co-engrafted with PBL and tumor cells. This enhancement was observed in both an allogeneic setting (in which the PBL were allogeneic with respect to the tumor) and an autologous setting (in which the PBL and tumor were from the same patient). These results sustain the notion that human anti-tumor immune response can be augmented (in vivo) by blocking the interaction between CTLA-4 and B7.

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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CTLA-4:

Cytotoxic T Lymphocyte associated Antigen 4

SCID:

Severe combined immunodeficient

MLR:

Mixed lymphocyte reaction

PBL:

Peripheral blood leukocytes

DC:

Dendritic cells

NK:

Natural killer cells

References

  1. Boon T, van der Bruggen P (1996) Human tumor antigens recognized by T lymphocytes. J Exp Med 183:725–729

    Google Scholar 

  2. Rosenberg SA (1999) A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10:281–287

    Google Scholar 

  3. Cohen PA, Peng L, Plautz GE, et al. (2000) CD4+ T cells in adoptive immunotherapy and the indirect mechanism of tumor rejection. Critical Reviews in Immunology 20:17–56

    Google Scholar 

  4. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273

    Google Scholar 

  5. Pardoll D (2003) Does the immune system see tumors as foreign or self? Annu Rev Immunol 21:807–839

    Google Scholar 

  6. Perez-Diaz A, Spiess PJ, Restifo NP, et al. (2002) Intensity of the vaccine-elicited immune response determines tumor clearance. J Immunol 168:338–347

    Google Scholar 

  7. Chambers CA, Allison JP (1997) Co-stimulation in T cell responses. Curr Opin Immunol 9:396–404

    Google Scholar 

  8. Mueller DL, Jenkins MK, Schwartz RH (1989) Clonal expansion versus functional clonal inactivation: A costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol 7:445–480

    Google Scholar 

  9. Sharpe AH, Freeman GJ (2002) The B7-CD28 superfamily. Nat Immunol 2:116–126

    Google Scholar 

  10. Brunet JF, Denizot F, Luciani MF, et al (1987) A new member of the immunoglobulin superfamily- CTLA-4. Nature 328:267–270

    Google Scholar 

  11. Linsley PS, Brady W, Urnes M, et al. (1991) CTLA-4 is a second receptor for the B-cell activation antigen B7. J Exp Med 174:561–569

    Google Scholar 

  12. Linsley PS, Greene JL, Brady W, et al (1994) Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1:793–801

    Google Scholar 

  13. van der Merwe PA, Bodian DL, Daenke S, et al. (1997) CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med 185:393–403

    Google Scholar 

  14. Walunas TL, Lenschow DJ, Bakker CY, et al. (1994) CLTA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413

    Google Scholar 

  15. Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T-cells to stimulation. J Exp Med 182:459–465

    Google Scholar 

  16. Waterhouse P, Penninger JM, Timms E, et al. (1995) CTLA-4 deficiency causes lymphoproliferative disorder with early lethality. Science 1995; 270:985–988

    Google Scholar 

  17. Tivol EA, Borriello F, Schweitzer AN, et al. (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role for CLTA-4. Immunity 3:541–547

    Google Scholar 

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

    Google Scholar 

  19. Lee KH, Holdorf AD, Dustin ML, et al. (2002) T cell receptor signaling precedes immunological synapse formation. Science 295:1539–1542

    Google Scholar 

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

    Google Scholar 

  21. van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-CTLA-4 and GM-CSF producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 190:355–366

    Google Scholar 

  22. Bankert RB, Egilmez NK, Hess SD (2001) Human/SCID chimeric models for preclinical evaluation of anti-cancer therapies: Applications, limitations and future directions. Trends Immunol 22:368–393

    Google Scholar 

  23. Egilmez NK, Hess SD, Chen FA, et al. (2002) CD4+ effector T-cells mediate an indirect IL-12 and IFN-gamma-dependent suppression of autologous lung tumor xenografts in SCID mice. Cancer Res 62:2611–2617

    Google Scholar 

  24. Iwanuma Y, Chen FA, Egilmez NK, et al (1997) Antitumor immune response of human peripheral blood lymphocytes co-engrafted with tumor nito severe immunodeficient mice. Cancer Research 57:2937–2942

    Google Scholar 

  25. Linsley PS, Greene JL, Tan P, et al. (1992) Co-expression and functional cooperation of CTLA-4 and CD28 on activated T-lymphocytes. J Exp Med 176:1595–1604

    Google Scholar 

  26. Bender A, Sapp M, Schuler G, et al. (1996) Improved methods for the generation of dendritic cells from non-proliferating progenitors in human blood. J Immunol Methods 196:121–135

    Google Scholar 

  27. Mosmann T (1993) Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Google Scholar 

  28. Liu Y (1997) Is CTLA-4 a negative regulator for T-cell activation? Immunol Today 18:569–72

    Google Scholar 

  29. Thompson CB, Allison JP (1997) The emerging role of CTLA-4 as an immune attenuator. Immunity 7:445–450

    Google Scholar 

  30. Yang Y (1997) Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte associated molecule-4 blockade: The effect is manfiested only at the restricted tumor-bearing stages. Cancer Res 57:4036–4041

    Google Scholar 

  31. Hurwitz AA, Yu TF, Leach DR, Allison JP (1998) CLTA-4 blockade synergizes with tumor-derived GM-CSF for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci USA (10067–10071)

  32. Hurwitz AA, Foster BA, Kwon ED, et al (2000) Combination immunotherapy of primary prostate cancer ina transgenic mouse model using CTLA-4 blockade. Cancer Res 60:2444–2448

    Google Scholar 

  33. Mokyr MB, Kalinchenko T, Gorelik L, Bluestone JA (1998) Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice. Cancer Research 58:5301–5304

    Google Scholar 

  34. Phan GQ, Yang JC, Sherry RM, et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377

    Google Scholar 

  35. Hodi FS, Mihm MC, Soiffer RJ, et al (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 100:4712–4717

    Google Scholar 

Download references

Acknowledgments

The authors thank James P. Allison for reading the manuscript and providing critical comments and helpful suggestions. We greatly appreciate the help from Mr. Robert Parsons and the DLAR staff at RPCI for their help and support with the SCID mouse colony. We are grateful to Dr. Ron Gladue from Pfizer, Inc. for the gift of the P2 anti-CTLA-4 antibody and the isotype control antibody and to Dr. Robert Peach from Bristol-Myers Squibb who supplied us with the CTLA-4 Ig fusion protein, the L6 fusion protein control and the anti-CTLA-4 antibody 10A8. We thank Ms. Sandra Yokota and Ms. Jenni Loyall for their excellent technical support and Cheryl Zuber for helping with the preparation and typing of this manuscript.This work was supported in part by U.S. Public Health Service Grants CA79879 and CA96528 (to R.B.B.).

Author information

Authors and Affiliations

  1. Department of Surgery, 3304 Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA

    Michael S. Sabel

  2. Department of Microbiology, State University of NY at Buffalo, Buffalo, NY, 14214, USA

    Stephen D. Hess, Nejat K. Egilmez & Richard B. Bankert

  3. Department Of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH, 03756, USA

    Thomas F. Conway Jr

  4. Department of Otolaryngology, Division of Head and Neck Surgery, NYU Medical Center, New York, NY, 10016, USA

    Fang-An Chen

Authors
  1. Michael S. Sabel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen D. Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nejat K. Egilmez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas F. Conway Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fang-An Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard B. Bankert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael S. Sabel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabel, M.S., Hess, S.D., Egilmez, N.K. et al. CTLA-4 blockade augments human T lymphocyte-mediated suppression of lung tumor xenografts in SCID mice. Cancer Immunol Immunother 54, 944–952 (2005). https://doi.org/10.1007/s00262-005-0668-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-005-0668-3

Keywords

Search

Navigation