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Contenido archivado el 2024-06-16

Cellular And Molecular Mechanisms Of Cross-Presentation In Epitope Spreading Following Immune Responses To Anti-Tumor Vaccines

Final Activity Report Summary - EPISPREAD_XP (Cellular And Molecular Mechanisms Of Cross-Presentation In Epitope Spreading Following Immune Responses To Anti-Tumor Vaccines)

In the project 'EPISPREAD_XP' Dr A.K. Nussbaum and Prof. S. Amigorena attempted to elucidate mechanisms related to the 'epitope spreading' phenomenon. The term refers to the observation of secondary immune responses after the treatment of cancer patients with tumour-specific vaccines. Epitope spreading leads to the induction of additional immune responses against the tumour which have been observed to be beneficial for the patient. It is therefore conceivable that understanding epitope spreading could lead to more efficient vaccine-based cancer therapies.

Our goal was to model epitope spreading in mice and use this model to ask questions on the related cellular and molecular mechanisms. Our mouse (C57BL/6) model was based on the mouse melanoma tumour B16, expressing several known endogenous and exogenous (model) tumour antigens. Our vaccine protocol was a mixture of prophylactic and therapeutic vaccines. The vaccines consisted of short peptides representing tumour antigen epitopes of killer T lymphocytes (CD8+ T cells) and short immunestimulatory deoxyribonucleic acid (DNA) sequences (ODN CpG), which functioned as adjuvants.

The project proved very challenging, mostly because of the very nature of the epitope spreading immune response. It was very weak, thus often at the limit of detection. However, we did succeed in establishing the model. When mice bearing B16 melanoma tumours were vaccinated with the tumour antigen trp2, strong CD8+ T cell responses against the vaccine were measured. However, we also observed a CD8+ T response to a model tumour antigen which was not present in the vaccine, as a result of epitope spreading.

This new experimental tool was ready for exploitation to elucidate underlying cellular and molecular mechanisms. Knowledge on such mechanisms would it easier to improve therapeutic cancer vaccines. Our mouse model for epitope spreading was the first of its kind. All employed epitopes were known, thus allowing for much focused monitoring of all the CD8+ T cell responses involved. This fact was expected to prove very helpful in case of elucidating how the epitope spreading response was initially triggered.