Immunotherapeutic Targeting of Membrane Hsp70-Expressing Tumors Using Recombinant Human Granzyme BReportar como inadecuado




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Background

We have previously reported that human recombinant granzyme B grB mediates apoptosis in membrane heat shock protein 70 Hsp70-positive tumor cells in a perforin-independent manner.

Methodology-Principal Findings

Optical imaging of uptake kinetics revealed co-localization of grB with recycling endosomes Rab9-11 as early as 5 min after internalization, with late endosomes Rab7 after 30 min, and the lysosomal compartment LAMP1-2 after 60 to 120 min. Active caspase-3-mediated apoptosis was induced in mouse CT26 monolayer cells and 3D tumor spheroids, but not in normal mouse endothelial cells. Granzyme B selectively reduced the proportion of membrane Hsp70-positive cells in CT26 tumor spheroids. Consecutive i.v. injections of recombinant human grB into mice bearing membrane Hsp70-positive CT26 tumors resulted in significant tumor suppression, and a detailed inspection of normal mouse organs revealed that the administration of anti-tumoral concentrations of grB elicited no clinicopathological changes.

Conclusions-Significance

These findings support the future clinical evaluation of human grB as a potential adjuvant therapeutic agent, especially for treating immunosuppressed patients that bear membrane Hsp70-positive tumors.



Autor: Mathias Gehrmann , Stefan Stangl , Andreas Kirschner, Gemma A. Foulds, Wolfgang Sievert, Brigitte T. Doß, Axel Walch, Alan G. Po

Fuente: http://plos.srce.hr/



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