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J. Exp. Med.,
Volume 188, Number 9, November 2, 1998 1553-1561
By
-
ugi*
From the * T Cell Development Laboratory and the 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.
Swim Across America Laboratory, Immunology
Program, Memorial Sloan-Kettering Cancer Center, New York 10021; and the § Division of Geriatrics
and Gerontology, Cornell University Medical College, New York 10021
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