Unmasking cryptic epitopes after loss of immunodominant tumor antigen expression through epitope spreading

Kate M. Lally, Simone Mocellin, Galen A. Ohnmacht, Mai Britt Nielsen, Maria Bettinotti, Monica C. Panelli, Vladia Monsurro, Francesco M. Marincola

Research output: Contribution to journalArticle

Abstract

The basis of intra-tumoral and systemic T cell reactivity toward cancer remains unclear. In particular the role that peripheral stimuli, whether endogenous or exogenous, play in shaping acquired immune response toward cancer remains poorly understood. In this study we document the surfacing of systemic immune reactivity toward a cryptic epitope from the MAGE-12 gene (MAGE-12:170-178), after temporary regression of a single melanoma metastasis, in response to gp100/PMel17-specific vaccination. This emergence was unlikely related to unusually high expression of MAGE-12 by the tumor, by the influence of analog epitopes to MAGE-12:170-178. Because MAGE-12 was unlikely to be expressed at sites other than the tumor, the demonstration of MAGE-12:170-178 reactivity in post- but not pre-vaccination circulating lymphocytes suggests that the systemically observed immune response was influenced by events induced by the vaccine at tumor site or draining lymph nodal areas. Possibly, as suggested by pre-clinical models, immunologic ignorance is the default response toward cancer in humans unless unusual stimulatory conditions occur in peripheral tissues. Surfacing of MAGE-12 specificity occurred in association with loss of gp100/PMel17 targeted by the vaccine. This finding suggests that vaccinations might have effects beyond their intrinsic specificity and may trigger broader immune responses through epitope spreading by inducing changes within the tumor microenvironment. This may have important practical implication for the development of immunization strategies.

Original languageEnglish (US)
Pages (from-to)841-847
Number of pages7
JournalInternational Journal of Cancer
Volume93
Issue number6
DOIs
StatePublished - Sep 15 2001
Externally publishedYes

Keywords

  • Epitope spreading
  • Immunotherapy
  • MAGE
  • Tumor antigens
  • Vaccines

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Lally, K. M., Mocellin, S., Ohnmacht, G. A., Nielsen, M. B., Bettinotti, M., Panelli, M. C., Monsurro, V., & Marincola, F. M. (2001). Unmasking cryptic epitopes after loss of immunodominant tumor antigen expression through epitope spreading. International Journal of Cancer, 93(6), 841-847. https://doi.org/10.1002/ijc.1420