Heteroclitic immunization induces tumor immunity

Ruben Dyall, Wilbur B. Bowne, Lawrence W. Weber, Joel LeMaoult, Paul Szabo, Yoichi Moroi, Gregory Piskun, Jonathan J. Lewis, Alan N. Houghton, Janko Nikolić-Žugić

Research output: Contribution to journalArticlepeer-review

182 Scopus citations

Abstract

In tumor transplantation models in mice, cytotoxic T lymphocytes (CTLs) are typically the primary effector cells. CTLs recognize major histocompatibility complex (MHC) class I-associated peptides expressed by tumors, leading to tumor rejection. Peptides presented by cancer cells can originate from viral proteins, normal self-proteins regulated during differentiation, or altered proteins derived from genetic alterations. However, many tumor peptides recognized by CTLs are poor immunogens, unable to induce activation and differentiation of effector CTLs. We used MHC binding motifs and the knowledge of class I:peptide:TCR structure to design heteroclitic CTL vaccines that exploit the expression of poorly immunogenic tumor peptides. The in vivo potency of this approach was demonstrated using viral and self-(differentiation) antigens as models. First, a synthetic variant of a viral antigen was expressed as a tumor antigen, and heteroclitic immunization with peptides and DNA was used to protect against tumor challenge and elicit regression of 3-d tumors. Second, a peptide from a relevant self-antigen of the tyrosinase family expressed by melanoma cells was used to design a heteroclitic peptide vaccine that successfully induced tumor protection. These results establish the in vivo applicability of heteroclitic immunization against tumors, including immunity to poorly immunogenic self-proteins.

Original languageEnglish (US)
Pages (from-to)1553-1561
Number of pages9
JournalJournal of Experimental Medicine
Volume188
Issue number9
DOIs
StatePublished - Nov 2 1998
Externally publishedYes

Keywords

  • Cytotoxic T lymphocyte
  • Heteroclitic peptides
  • Major histocompatibility complex class I
  • Peptide vaccines
  • Tumors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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