Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer

Abstract

Antigen-specific CD8+ T-cell tolerance, induced by myeloid-derived suppressor cells (MDSCs), is one of the main mechanisms of tumor escape. Using in vivo models, we show here that MDSCs directly disrupt the binding of specific peptide–major histocompatibility complex (pMHC) dimers to CD8-expressing T cells through nitration of tyrosines in a T-cell receptor (TCR)-CD8 complex. This process makes CD8-expressing T cells unable to bind pMHC and to respond to the specific peptide, although they retain their ability to respond to nonspecific stimulation. Nitration of TCR-CD8 is induced by MDSCs through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact. Molecular modeling suggests specific sites of nitration that might affect the conformational flexibility of TCR-CD8 and its interaction with pMHC. These data identify a previously unknown mechanism of T-cell tolerance in cancer that is also pertinent to many pathological conditions associated with accumulation of MDSCs.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: MSDCs disrupt binding of pMHC to CD8+ T cells.
Figure 2: Mechanism of MDSC-induced T-cell tolerance.
Figure 3: Effect of peroxynitrite donor on specific CD8+ T-cell activity.
Figure 4: Role of MDSCs in the nitration of tyrosine in CD8+ T cells.
Figure 5: Interaction between MDSCs and CD8+ T cells.
Figure 6: MDSCs induce CD8+ T-cell tolerance in tumor-bearing mice.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Sotomayor, E.M. et al. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat. Med. 5, 780–787 (1999).

    Article  CAS  Google Scholar 

  3. Cuenca, A. et al. Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens. Cancer Res. 63, 9007–9015 (2003).

    CAS  PubMed  Google Scholar 

  4. Kusmartsev, S., Nagaraj, S. & Gabrilovich, D.I. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J. Immunol. 175, 4583–4592 (2005).

    Article  CAS  Google Scholar 

  5. Huang, B. et al. 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, 1123–1131 (2006).

    Article  CAS  Google Scholar 

  6. Serafini, P., Borrello, I. & Bronte, V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin. Cancer Biol. 16, 53–65 (2006).

    Article  CAS  Google Scholar 

  7. Gabrilovich, D. The mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat. Rev. Immunol. 4, 941–952 (2004).

    Article  CAS  Google Scholar 

  8. Kusmartsev, S. & Gabrilovich, D.I. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol. Immunother. 55, 237–245 (2006).

    Article  Google Scholar 

  9. Sinha, P., Clements, V.K., Miller, S. & Ostrand-Rosenberg, S. Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol. Immunother. 54, 1137–1142 (2005).

    Article  CAS  Google Scholar 

  10. Almand, B. et al. Increased production of immature myeloid cells in cancer patients. A mechanism of immunosuppression in cancer. J. Immunol. 166, 678–689 (2001).

    Article  CAS  Google Scholar 

  11. Schmielau, J. & Finn, O.J. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res. 61, 4756–4760 (2001).

    CAS  PubMed  Google Scholar 

  12. Zea, A.H. et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 65, 3044–3048 (2005).

    Article  CAS  Google Scholar 

  13. Appleman, L.J., Tzachanis, D., Grader-Beck, T., van Puijenbroek, A.A. & Boussiotis, V.A. Helper T cell anergy: from biochemistry to cancer pathophysiology and therapeutics. J. Mol. Med. 78, 673–683 (2001).

    Article  CAS  Google Scholar 

  14. Steinman, R.M. & Nussenzweig, M.C. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc. Natl. Acad. Sci. USA 99, 351–358 (2002).

    Article  CAS  Google Scholar 

  15. Kusmartsev, S. & Gabrilovich, D.I. Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J. Leukoc. Biol. 74, 186–196 (2003).

    Article  CAS  Google Scholar 

  16. Dutz, J.P., Tsomides, T.J., Kageyama, S., Rasmussen, M.H. & Eisen, H.N. A cytotoxic T lymphocyte clone can recognize the same naturally occurring self peptide in association with a self and nonself class I MHC protein. Mol. Immunol. 31, 967–975 (1994).

    Article  CAS  Google Scholar 

  17. Udaka, K., Wiesmuller, K.H., Kienle, S., Jung, G. & Walden, P. Self-MHC-restricted peptides recognized by an alloreactive T lymphocyte clone. J. Immunol. 157, 670–678 (1996).

    CAS  PubMed  Google Scholar 

  18. Quinn, M.T. The neutrophils respiratory burst oxidase. in The Neutrophils. New Outlook for Old Cells (ed. Gabrilovich, D.I.) 35–85 (Imperial College Press, London, 2005).

    Chapter  Google Scholar 

  19. Squadrito, G.L. & Pryor, W.A. The formation of peroxynitrite in vivo from nitric oxide and superoxide. Chem. Biol. Interact. 96, 203–206 (1995).

    Article  CAS  Google Scholar 

  20. Kusmartsev, S., Nefedova, Y., Yoder, D. & Gabrilovich, D.I. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J. Immunol. 172, 989–999 (2004).

    Article  CAS  Google Scholar 

  21. Regoli, F. & Winston, G.W. Quantification of total oxidant scavenging capacity of antioxidants for peroxynitrite, peroxyl radicals, and hydroxyl radicals. Toxicol. Appl. Pharmacol. 156, 96–105 (1999).

    Article  CAS  Google Scholar 

  22. Balavoine, G.G. & Geletii, Y.V. Peroxynitrite scavenging by different antioxidants. Part I: convenient assay. Nitric Oxide 3, 40–54 (1999).

    Article  CAS  Google Scholar 

  23. Smyth, M. et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to the interferon-γ-dependent natural killer cell protection from tumor metastasis. J. Exp. Med. 193, 661–670 (2000).

    Article  Google Scholar 

  24. Kusmartsev, S. & Gabrilovich, D. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J. Immunol. 174, 4880–4891 (2005).

    Article  CAS  Google Scholar 

  25. Zingarelli, B. et al. Oxidation, tyrosine nitration and cytostasis induction in the absence of inducible nitric oxide synthase. Int. J. Mol. Med. 1, 787–795 (1998).

    CAS  PubMed  Google Scholar 

  26. Haqqani, A.S., Kelly, J.F. & Birnboim, H.C. Selective nitration of histone tyrosine residues in vivo in mutatect tumors. J. Biol. Chem. 277, 3614–3621 (2002).

    Article  CAS  Google Scholar 

  27. Quint, P., Reutzel, R., Mikulski, R., McKenna, R. & Silverman, D.N. Crystal structure of nitrated human manganese superoxide dismutase: mechanism of inactivation. Free Radic. Biol. Med. 40, 453–458 (2006).

    Article  CAS  Google Scholar 

  28. Wilkinson, I.B., MacCallum, H., Cockcroft, J.R. & Webb, D.J. Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo. Br. J. Clin. Pharmacol. 53, 189–192 (2002).

    Article  CAS  Google Scholar 

  29. Nikitina, E.Y. et al. An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53. Gene Ther. 9, 345–352 (2002).

    Article  CAS  Google Scholar 

  30. Pandit, R., Lathers, D., Beal, N., Garrity, T. & Young, M. CD34+ immune suppressive cells in the peripheral blood of patients with head and neck cancer. Ann. Otol. Rhinol. Laryngol. 109, 749–754 (2000).

    Article  CAS  Google Scholar 

  31. Bronte, V., Serafini, P., Appoloni, E. & Zanovello, P. Tumor-induced immune dysfunctions caused by myeloid suppressor cells. J. Immunother. 24, 431–446 (2001).

    Article  CAS  Google Scholar 

  32. Melani, C., Chiodoni, C., Forni, G. & Colombo, M.P. Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 102, 2138–2145 (2003).

    Article  CAS  Google Scholar 

  33. Makarenkova, V.P., Bansal, V., Matta, B.M., Perez, L.A. & Ochoa, J.B. CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J. Immunol. 176, 2085–2094 (2006).

    Article  CAS  Google Scholar 

  34. Mencacci, A. et al. CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis. J. Immunol. 169, 3180–3190 (2002).

    Article  CAS  Google Scholar 

  35. Atochina, O., Daly-Angel, T., Piskorska, D. & Harn, D. A shistosome expressed immunomodulatory glycoconjugate expand peritoneal Gr1+ macrophages that suppress naive CD4+ T cell proliferation via an interferon-γ and nitric oxide dependent mechanism. J. Immunol. 167, 4293–4302 (2001).

    Article  CAS  Google Scholar 

  36. Fahmy, T.M., Bieler, J.G., Edidin, M. & Schneck, J.P. Increased TCR avidity after T cell activation: a mechanism for sensing low-density antigen. Immunity 14, 135–143 (2001).

    CAS  PubMed  Google Scholar 

  37. Maile, R. et al. Peripheral “CD8 tuning” dynamically modulates the size and responsiveness of an antigen-specific T cell pool in vivo. J. Immunol. 174, 619–627 (2005).

    Article  CAS  Google Scholar 

  38. Drake, D.R., III, Ream, R.M., Lawrence, C.W. & Braciale, T.J. Transient loss of MHC class I tetramer binding after CD8+ T cell activation reflects altered T cell effector function. J. Immunol. 175, 1507–1515 (2005).

    Article  CAS  Google Scholar 

  39. Alvarez, B. & Radi, R. Peroxynitrite reactivity with amino acids and proteins. Amino Acids 25, 295–311 (2003).

    Article  CAS  Google Scholar 

  40. De Santo, C. et al. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc. Natl. Acad. Sci. USA 102, 4185–4190 (2005).

    Article  CAS  Google Scholar 

  41. Sha, W.C. et al. Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature 335, 271–274 (1988).

    Article  CAS  Google Scholar 

  42. Kusmartsev, S. et al. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 63, 4441–4449 (2003).

    CAS  PubMed  Google Scholar 

  43. Gabrilovich, D.I., Velders, M., Sotomayor, E. & Kast, W.M. Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J. Immunol. 166, 5398–5406 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Kusmartsev for assistance at the beginning of this project and J. DeComarmond for technical assistance with manuscript preparation. This work was supported by the National Institutes of Health (grant RO1CA 84488 to D.I.G.) and, in part, by the Analytic Microscopy and Flow Cytometry Core Facility at the H. Lee Moffitt Cancer Center.

Author information

Authors and Affiliations

Authors

Contributions

S.N. performed most of the experiments, analyzed data and wrote the manuscript; K.G. performed some of binding experiments; V.P. contributed to overall research design and molecular modeling analysis; L.K. performed molecular modeling analysis; S.S. performed molecular modeling analysis; L.K. performed immunohistology in human tissues; D.H. performed immunohistology in mouse tissues; J.S. contributed to overall research design and analysis; D.I.G. designed the experiments, analyzed the data, wrote the manuscript and supervised the project.

Corresponding author

Correspondence to Dmitry I Gabrilovich.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Experimental model of MDSC-induced T-cell tolerance. (PDF 259 kb)

Supplementary Fig. 2

MSDC disrupt binding of pMHC to to CD8+ T cells in 2C models. (PDF 21 kb)

Supplementary Fig. 3

Positioning of the potential sites of a TCR/pMHC/CD8 nitration. (PDF 143 kb)

Supplementary Fig. 4

Effect of nitration of tyrosines in TCR and CD8 molecules. (PDF 127 kb)

Supplementary Fig. 5

Nitrotyrosine positive CD8+ T cells in lymphoid tissues. (PDF 59 kb)

Supplementary Fig. 6

Duration of CD8+ T-cell tolerance induced by MDSC. (PDF 16 kb)

Supplementary Fig. 7

Myeloid derived suppressor cells associate with T cells. (PDF 91 kb)

Supplementary Fig. 8

Effect of uric acid on T-cell activation in vivo. (PDF 67 kb)

Supplementary Discussion (PDF 59 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagaraj, S., Gupta, K., Pisarev, V. et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 13, 828–835 (2007). https://doi.org/10.1038/nm1609

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1609

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing