Manolis Pasparakis - A 8

Immunogenic properties of necroptosis and apoptosis in stimulating anti-tumor immunity

Abstract

The development of effective anti-tumour immunity is capable of restricting tumour development and causing tumour regression. The recent development of antibodies blocking specific checkpoints in T cell activation, such the anti-PD-1 and anti-PD-L1 antibodies, has revolutionized cancer immunotherapy, leading to spectacular success in some patients. However, the effectiveness of the current protocols is restricted to a small subset of patients for reasons that are not understood. Therefore, a better understanding of the mechanisms determining anti-tumour immune responses is required in order to develop better protocols inducing effective anti-tumour immunity in the majority or hopefully all the patients. Death of tumour cells has been shown to induce anti-tumour immunity but it remains unclear whether different types of cell death have different immunogenic properties. Here we propose to study the effect of specific types of tumour cell death on anti-tumour immunity. We will focus particularly on necroptosis, a type of regulated necrotic cell death induced by RIPK3 and its substrate MLKL, which is highly immunogenic due to the massive release of DAMPs. We will compare the effect of tumour cell necroptosis with that of apoptosis in eliciting anti-tumour immunity, in a mouse model of autochthonous melanoma development. We will also study the role of necroptosis and apoptosis when combined with anti-PD-1 blocking antibodies in order to determine the potential synergistic effect of tumour cell death with immunotherapy protocols based on T cell activation checkpoint inhibitors.

Clinical/medical relevance and sustainability in disease understanding

Our studies aim to address the potential role of specific types of tumour cell death, namely necroptosis and apoptosis, in triggering anti-tumour immunity, and to explore their potential synergistic effect when combined with T cell activation checkpoint inhibitors. Our results may lead to the development of better immunotherapy protocols combining agents inducing specific types of cancer cell death with checkpoint inhibitors.


Prof. Dr. rer. nat. Manolis Pasparakis

Institute for Genetics

Prof. Dr. rer. nat. Manolis Pasparakis

Principal Investigator A 8

pasparakis@uni-koeln.de

Work +49 221 478 84351

CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne

http://www.genetik.uni-koeln.de/groups/Pasparakis/

Publications - Manolis Pasparakis

Link to PubMed