Skip to main content

Advertisement

SpringerLink
Log in

Uveal melanoma cell-based vaccines express MHC II molecules that traffic via the endocytic and secretory pathways and activate CD8+ cytotoxic, tumor-specific T cells

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

Abstract

We are exploring cell-based vaccines as a treatment for the 50% of patients with large primary uveal melanomas who develop lethal metastatic disease. MHC II uveal melanoma vaccines are MHC class I+ uveal melanoma cells transduced with CD80 genes and MHC II genes syngeneic to the recipient. Previous studies demonstrated that the vaccines activate tumor-specific CD4+ T cells from patients with metastatic uveal melanoma. We have hypothesized that vaccine potency is due to the absence of the MHC II-associated invariant chain (Ii). In the absence of Ii, newly synthesized MHC II molecules traffic intracellularly via a non-traditional pathway where they encounter and bind novel tumor peptides. Using confocal microscopy, we now confirm this hypothesis and demonstrate that MHC II molecules are present in both the endosomal and secretory pathways in vaccine cells. We also demonstrate that uveal melanoma MHC II vaccines activate uveal melanoma-specific, cytolytic CD8+ T cells that do not lyse normal fibroblasts or other tumor cells. Surprisingly, the CD8+ T cells are cytolytic for HLA-A syngeneic and MHC I-mismatched uveal melanomas. Collectively, these studies demonstrate that MHC II uveal melanoma vaccines are potent activators of tumor-specific CD4+ and CD8+ T cells and suggest that the non-conventional intracellular trafficking pattern of MHC II may contribute to their enhanced immunogenicity. Since MHC I compatibility is unnecessary for the activation of cytolytic CD8+ T cells, the vaccines could be used in uveal melanoma patients without regard to MHC I genotype.

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

Similar content being viewed by others

References

  1. Aichinger G, Karlsson L, Jackson MR, Vestberg M, Vaughan JH, Teyton L, Lechler RI, Peterson PA (1997) Major histocompatibility complex class II-dependent unfolding, transport, and degradation of endogenous proteins. J Biol Chem 272:29127–29136

    Article  PubMed  CAS  Google Scholar 

  2. 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 94:6886–6891

    Article  PubMed  CAS  Google Scholar 

  3. Armstrong TD, Clements VK, Ostrand-Rosenberg S (1998) MHC class II-transfected tumor cells directly present antigen to tumor-specific CD4+ T lymphocytes. J Immunol 160:661–666

    PubMed  CAS  Google Scholar 

  4. Benaroch P, Yilla M, Raposo G, Ito K, Miwa K, Geuze HJ, Ploegh HL (1995) How MHC class II molecules reach the endocytic pathway. EMBO J 14:37–49

    PubMed  CAS  Google Scholar 

  5. Berger AC, Roche PA (2009) MHC class II transport at a glance. J Cell Sci 122:1–4

    Article  PubMed  CAS  Google Scholar 

  6. Bikoff EK, Germain RN, Robertson EJ (1995) Allelic differences affecting invariant chain dependency of MHC class II subunit assembly. Immunity 2:301–310

    Article  PubMed  CAS  Google Scholar 

  7. Bikoff EK, Huang LY, Episkopou V, van Meerwijk J, Germain RN, Robertson EJ (1993) Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression. J Exp Med 177:1699–1712

    Article  PubMed  CAS  Google Scholar 

  8. Boes M, Cerny J, Massol R, Op den Brouw M, Kirchhausen T, Chen J, Ploegh HL (2002) T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418:983–988

    Article  PubMed  CAS  Google Scholar 

  9. 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 67:4499–4506

    Article  PubMed  CAS  Google Scholar 

  10. Busch R, Rinderknecht CH, Roh S, Lee AW, Harding JJ, Burster T, Hornell TM, Mellins ED (2005) Achieving stability through editing and chaperoning: regulation of MHC class II peptide binding and expression. Immunol Rev 207:242–260

    Article  PubMed  CAS  Google Scholar 

  11. Chamuleau ME, Ossenkoppele GJ, van de Loosdrecht AA (2006) MHC class II molecules in tumour immunology: prognostic marker and target for immune modulation. Immunobiology 211:619–625

    Article  PubMed  CAS  Google Scholar 

  12. Chamuleau ME, Souwer Y, Van Ham SM, Zevenbergen A, Westers TM, Berkhof J, Meijer CJ, van de Loosdrecht AA, Ossenkoppele GJ (2004) Class II-associated invariant chain peptide expression on myeloid leukemic blasts predicts poor clinical outcome. Cancer Res 64:5546–5550

    Article  PubMed  CAS  Google Scholar 

  13. 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 64:1867–1874

    Article  PubMed  CAS  Google Scholar 

  14. Dodi AI, Brett S, Nordeng T, Sidhu S, Batchelor RJ, Lombardi G, Bakke O, Lechler RI (1994) The invariant chain inhibits presentation of endogenous antigens by a human fibroblast cell line. Eur J Immunol 24:1632–1639

    Article  PubMed  CAS  Google Scholar 

  15. Elliott EA, Drake JR, Amigorena S, Elsemore J, Webster P, Mellman I, Flavell RA (1994) The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules. J Exp Med 179:681–694

    Article  PubMed  CAS  Google Scholar 

  16. Fukuda M (2008) Regulation of secretory vesicle traffic by Rab small GTPases. Cell Mol Life Sci 65:2801–2813

    Article  PubMed  CAS  Google Scholar 

  17. Huang XQ, Mitchell MS, Liggett PE, Murphree AL, Kan-Mitchell J (1994) Non-fastidious, melanoma-specific CD8+ cytotoxic T lymphocytes from choroidal melanoma patients. Cancer Immunol Immunother 38:399–405

    PubMed  CAS  Google Scholar 

  18. Kan-Mitchell J, Liggett PE, Harel W, Steinman L, Nitta T, Oksenberg JR, Posner MR, Mitchell MS (1991) Lymphocytes cytotoxic to uveal and skin melanoma cells from peripheral blood of ocular melanoma patients. Cancer Immunol Immunother 33:333–340

    Article  PubMed  CAS  Google Scholar 

  19. Kenty G, Bikoff EK (1999) BALB/c invariant chain mutant mice display relatively efficient maturation of CD4+ T cells in the periphery and secondary proliferative responses elicited upon peptide challenge. J Immunol 163:232–241

    PubMed  CAS  Google Scholar 

  20. Kujala E, Makitie T, Kivela T (2003) Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci 44:4651–4659

    Article  PubMed  Google Scholar 

  21. Lechler R, Aichinger G, Lightstone L (1996) The endogenous pathway of MHC class II antigen presentation. Immunol Rev 151:51–79

    Article  PubMed  CAS  Google Scholar 

  22. Long EO, LaVaute T, Pinet V, Jaraquemada D (1994) Invariant chain prevents the HLA-DR-restricted presentation of a cytosolic peptide. J Immunol 153:1487–1494

    PubMed  CAS  Google Scholar 

  23. Miller J, Germain RN (1986) Efficient cell surface expression of class II MHC molecules in the absence of associated invariant chain. J Exp Med 164:1478–1489

    Article  PubMed  CAS  Google Scholar 

  24. Mooy CM, De Jong PT (1996) Prognostic parameters in uveal melanoma: a review. Surv Ophthalmol 41:215–228

    Article  PubMed  CAS  Google Scholar 

  25. 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 173:1085–1093

    PubMed  CAS  Google Scholar 

  26. Ostrand-Rosenberg S, Grusby MJ, Clements VK (2000) Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J Immunol 165:6015–6019

    PubMed  CAS  Google Scholar 

  27. Qi L, Rojas JM, Ostrand-Rosenberg S (2000) Tumor cells present MHC class II-restricted nuclear and mitochondrial antigens and are the predominant antigen presenting cells in vivo. J Immunol 165:5451–5461

    PubMed  CAS  Google Scholar 

  28. Rohn TA, Boes M, Wolters D, Spindeldreher S, Muller B, Langen H, Ploegh H, Vogt AB, Kropshofer H (2004) Upregulation of the CLIP self peptide on mature dendritic cells antagonizes T helper type 1 polarization. Nat Immunol 5:909–918

    Article  PubMed  CAS  Google Scholar 

  29. Rubio V, Stuge TB, Singh N, Betts MR, Weber JS, Roederer M, Lee PP (2003) Ex vivo identification, isolation and analysis of tumor-cytolytic T cells. Nat Med 9:1377–1382

    Article  PubMed  CAS  Google Scholar 

  30. Sekaly RP, Tonnelle C, Strubin M, Mach B, Long EO (1986) Cell surface expression of class II histocompatibility antigens occurs in the absence of the invariant chain. J Exp Med 164:1490–1504

    Article  PubMed  CAS  Google Scholar 

  31. Srivastava MK, Bosch JJ, Thompson JA, Ksander BR, Edelman MJ, Ostrand-Rosenberg S (2008) Lung cancer patients’ CD4(+) T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells. Cancer Immunol Immunother 57:1493–1504

    Article  PubMed  CAS  Google Scholar 

  32. Stumptner-Cuvelette P, Benaroch P (2002) Multiple roles of the invariant chain in MHC class II function. Biochim Biophys Acta 1542:1–13

    Article  PubMed  CAS  Google Scholar 

  33. 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 66:1147–1154

    Article  PubMed  CAS  Google Scholar 

  34. Thompson JA, Srivastava MK, Bosch JJ, Clements VK, Ksander BR, Ostrand-Rosenberg S (2008) The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor-reactive type 1 CD4+ T lymphocytes. Cancer Immunol Immunother 57:389–398

    Article  PubMed  CAS  Google Scholar 

  35. Tomazin R, Hill AB, Jugovic P, York I, van Endert P, Ploegh HL, Andrews DW, Johnson DC (1996) Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP. EMBO J 15:3256–3266

    PubMed  CAS  Google Scholar 

  36. Topilski I, Harmelin A, Flavell RA, Levo Y, Shachar I (2002) Preferential Th1 immune response in invariant chain-deficient mice. J Immunol 168:1610–1617

    PubMed  CAS  Google Scholar 

  37. Verbik DJ, Murray TG, Tran JM, Ksander BR (1997) Melanomas that develop within the eye inhibit lymphocyte proliferation. Int J Cancer 73:470–478

    Article  PubMed  CAS  Google Scholar 

  38. Viville S, Neefjes J, Lotteau V, Dierich A, Lemeur M, Ploegh H, Benoist C, Mathis D (1993) Mice lacking the MHC class II-associated invariant chain. Cell 72:635–648

    Article  PubMed  CAS  Google Scholar 

  39. Walseng E, Bakke O, Roche PA (2008) Major histocompatibility complex class II-peptide complexes internalize using a clathrin- and dynamin-independent endocytosis pathway. J Biol Chem 283:14717–14727

    Article  PubMed  CAS  Google Scholar 

  40. Woodman PG (2000) Biogenesis of the sorting endosome: the role of Rab5. Traffic 1:695–701

    Article  PubMed  CAS  Google Scholar 

  41. Wubbolts R, Fernandez-Borja M, Oomen L, Verwoerd D, Janssen H, Calafat J, Tulp A, Dusseljee S, Neefjes J (1996) Direct vesicular transport of MHC class II molecules from lysosomal structures to the cell surface. J Cell Biol 135:611–622

    Article  PubMed  CAS  Google Scholar 

  42. Zwart W, Griekspoor A, Kuijl C, Marsman M, van Rheenen J, Janssen H, Calafat J, van Ham M, Janssen L, van Lith M, Jalink K, Neefjes J (2005) Spatial separation of HLA-DM/HLA-DR interactions within MIIC and phagosome-induced immune escape. Immunity 22:221–233

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. J. Neefjes for his kind gift of the DR1β-eGFP pcDNA3 plasmid, Dr. J. Leach for use of her fluorescent microscope, Ms. C. Petty for assistance with the confocal microscopy, Ms. V. Clements for her excellent technical assistance, and Dr. P. Chen for his helpful discussions. These studies were supported by NIH R01CA52527, R01CA84232 (SOR), and NIH R01EY016486 (BRK). JJB was partially supported by post-doctoral fellowships from Fight for Sight, Inc., Rotterdamse Vereniging Blindenbelangen, Stichting Blindenhulp, Stichting Blinden-Penning, Stichting Dondersfonds, Stichting Nelly Reef Fund, Gratama Stichting, Stichting Admiraal van Kinsbergen Fonds, and Foundation ‘De Drie Lichten’. UKI was supported by a MARC-U-STAR training grant (NIH/NIGMS GM08663).

Author information

Authors and Affiliations

  1. Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, USA

    Jacobus J. Bosch, Uzoma K. Iheagwara, Sarah Reid, Minu K. Srivastava, Julie Wolf & Suzanne Ostrand-Rosenberg

  2. The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

    Jacobus J. Bosch & Bruce R. Ksander

  3. Sharett Institute of Oncology, Hadassah University Hospital, Jerusalem, Israel

    Michal Lotem

Authors
  1. Jacobus J. Bosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Uzoma K. Iheagwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah Reid
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Minu K. Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julie Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michal Lotem
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bruce R. Ksander
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Suzanne Ostrand-Rosenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suzanne Ostrand-Rosenberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bosch, J.J., Iheagwara, U.K., Reid, S. et al. Uveal melanoma cell-based vaccines express MHC II molecules that traffic via the endocytic and secretory pathways and activate CD8+ cytotoxic, tumor-specific T cells. Cancer Immunol Immunother 59, 103–112 (2010). https://doi.org/10.1007/s00262-009-0729-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-009-0729-0

Keywords

Search

Navigation