Centro de investigación del Cáncer - Comprehensive Cancer Center Research

Seminario CIC

Apoptosis and inflammation induced by the granule exocytosis pathway of killer cells: an alternative to overcome multidrug resistance of tumor cells to apoptosis

Ponente: JuliÃ¡n Pardo Investigador ARAID, Centro de Investigaciones BiomÃ©dicas de AragÃ³n (CIBA), Universidad de Zaragoza

TÃtulo: Apoptosis and inflammation induced by the granule exocytosis pathway of killer cells: an alternative to overcome multidrug resistance of tumor cells to apoptosis

DÃa: 30-05-2013 a las 12:30

Lugar: SalÃ³n de Actos del CIC

Abstract: Pathogens and tumour cells have evolved to counter act the host defense strategies to fight cancer and infection. Among them induction of apoptotic cell death by cytotoxic T (Tc) and Natural Killer (NK) cells is one of the main mechanisms used by the host immune system to eliminate transformed cells and intracellular pathogens. Tc and NK cells induce apoptosis in target cells by two main mechanisms: the death ligand/death receptor pathway (i.e. FasL and Apo2L/TRAIL) and the exocytosis of pre-formed cytotoxic granules (granule exocytosis pathway). Granule exocytosis consists of a transfer process in which the pore forming protein perforin (perf) releases a family of serin-proteases, the granzymes (gzms) into the cytosol of target cells, where they activate different pro-apoptotic cell death pathways. Although originally identified in Tc and NK cells, gzms have been now identified in several types of immune cells including T regulatory cells mast cells, macrophages, dendritic cells or basophils. Yet the biological function of gzms in these cells is unknown. Using in vivo mouse models and ex vivo systems we have shown that Tc cells use perf and gzmB to induce apoptosis in tumour cells by activating simultaneously several independent cell death pathways. These results indicate that killer cells expressing perf and gzmB have the potential to eliminate transformed cells with mutations that confer resistance to chemotherapy and radiotherapy. On the other hand we found that other gzms found in Tc and NK cells, like gzmA, has limited cytotoxic potential but regulate the inflammatory response in macrophages. Thus, the balance between inflammation and cell death induced by specific gzms of Tc and NK cells may have completely opposite effects on tumor development by eliminating tumor cells (gzmB) or by inducing a pro-inflammatory microenvironment (gzmA) that promotes tumor development. During the last years we have established human models to analyse the relevance of apoptosis and inflammation induced by Tc and NK cells during cancer development and, specially, for the treatment of hematological neoplasias with acquired drug resistance due to mutations in the apoptotic machinery. Specifically we have studied if allogeneic human NK cells, one of the most recent immunotherapy protocols to treat hematological cancers, are able to overcome drug resistance to apoptosis in hematological cancer cell lines as well as in cells from patients with B-CLL. The implication of our most recent results in the treatment of tumour cells that do not respond to chemotherapy will be discussed.

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