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From the Department of Immunohematology and Bloodbank, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

This study shows that induction of tumor-specific CD4⁺ T cells by vaccination with a specific viral T helper epitope, contained within a synthetic peptide, results in protective immunity against major histocompatibility complex (MHC) class II negative, virus-induced tumor cells. Protection was also induced against sarcoma induction by acutely transforming retrovirus. In contrast, no protective immunity was induced by vaccination with an unrelated T helper epitope. By cytokine pattern analysis, the induced CD4⁺ T cells were of the T helper cell 1 type. The peptide-specific CD4⁺ T cells did not directly recognize the tumor cells, indicating involvement of cross-priming by tumor-associated antigen-presenting cells. The main effector cells responsible for tumor eradication were identified as CD8⁺ cytotoxic T cells that were found to recognize a recently described immunodominant viral gag-encoded cytotoxic T lymphocyte (CTL) epitope, which is unrelated to the viral env-encoded T helper peptide sequence. Simultaneous vaccination with the tumor-specific T helper and CTL epitopes resulted in strong synergistic protection. These results indicate the crucial role of T helper cells for optimal induction of protective immunity against MHC class II negative tumor cells. Protection is dependent on tumor-specific CTLs in this model system and requires cross-priming of tumor antigens by specialized antigen-presenting cells. Thus, tumor-specific T helper epitopes have to be included in the design of epitope-based vaccines.

This study was financed by the Netherlands Cancer Foundation grants 93-560 and 97-1451.

Address correspondence to F. Ossendorp, Department of Immunohematology and Bloodbank, University Hospital Leiden, Bldg. 1, E3-Q, PO Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31-71-5263800; Fax: 31-71-5216751; E-mail: ossendorp{at}rullf2.medfac.leidenuniv.nl

¹ Abbreviations used in this paper: FMR, Friend, Moloney, Rauscher; gag-L, gag-leader; gp, glycoprotein; MoMSV, Moloney murine sarcoma and leukemia virus complex; MuLV, murine leukemia virus; n.s., not significant.

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