Danila Valmori
College of Physicians & Surgeons
New York, NY

Mechanisms of Protective Tumor Immunity

Whereas virtually any antigen expressing MHC class I+ cell can present tumor antigens to CD8+ T cells, only professional antigen-presenting cells (APC) have the capacity to prime tumor antigen specific naïve CD8+ T cells in vivo. Professional APC can acquire exogenous tumor antigens and present them via their own MHC class I molecules to CD8+ T cells in a process known as antigen cross-presentation (1). The precise molecular pathways leading to cross-priming, however, remain controversial (2), and even the relevance of tumor antigen cross-presentation for the induction of anti-tumor responses has been questioned (3-5). In this presentation, I will review the proposed molecular basis for cross-presentation, the APC subsets which are known to be involved in this phenomenon and the in vivo conditions which may result in cross-priming of tumor antigen specific CD8+ T cells versus cross-tolerance. I will then show recent evidence that vaccination of cancer patients with NY-ESO-1 recombinant protein, Montanide® ISA-51 and the TLR9 ligand CpG 7909, can result in the in vivo cross-priming of NY-ESO-1 specific CD8+ T cells able to recognize endogenously expressed NY-ESO-1 antigen, indicating that cross-presentation of tumor antigens is highly relevant for tumor immunotherapy and can occur, following activation of professional APC, in the presence of appropriate levels of integrated humoral and CD4+ T-cell responses. The presented data provide direct evidence of in vivo cross-priming of specific CD8+ T cells by a recombinant full-length tumor antigen vaccine in cancer patients and support the use of this type of formulation for the further development of efficient cancer vaccines.

References:

1. Heath WR, Belz GT, Behrens GM, et al. Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol Rev 2004.

2. Groothuis TA, Neefjes J. The many roads to cross-presentation. J Exp Med. 2005.

3. Ochsenbein AF, Sierro S, Odermatt B, et al. Roles of tumor localization, second signals and cross priming in cytotoxic T-cell induction. Nature 2001.

4. Chen W, Masterman KA, Basta S, Haeryfar SM, Dimopoulos N, Knowles B, Bennink JR, Yewdell JW. Cross-priming of CD8+ T cells by viral and tumor antigens is a robust phenomenon. Eur J Immunol. 2004.

5. Melief CJ. Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming? Eur J Immunol. 2003