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

AL Rerole

Alan G. Pockley

Andreas Kirschner

Axel Walch

Brigitte T. Doß

C Botzler

C Gross

D Kaiserman

D Schilling

DR Ciocca

E Schmitt

FC Kurschus

G MacDonald

G Multhoff

Gabriele Multhoff

Gemma A. Foulds

H Dertinger

J Friedrich

J Nylandsted

J Sun

J Thiery

JA Trapani

K Pfister

L Chavez-Galan

M Gehrmann

M Wang

Mathias Gehrmann

Michael Platten

MS Buzza

RZ Lin

S Balkow

S Mahrus

S Stangl

SP Cullen

Stefan Stangl

SW Krause

U Giesubel

V Milani

WA Boivin

Wolfgang Sievert

Y Liu

Z Xia

PLoS ONE

English

PubMed

Gehrmann, M

Stangl, S

Kirschner, A

Foulds, GA

Sievert, W

Doß, BT

Walch, A

Pockley, AG

Multhoff, G

Nottingham Trent Institutional Repository (IRep)

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Cell surface-bound heat shock protein 70 (Hsp70) mediates perforin-independent apoptosis by specific binding and uptake of granzyme B.

Concerted action of the FasL/Fas and perforin/granzyme A and B pathways is mandatory for the development of early viral hepatitis but not for recovery from viral infection.

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Tumor-specific Hsp70 plasma membrane localization is enabled by the glycosphingolipid Gb3. PLos One 3:

Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B

BackgroundWe 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 findingsOptical 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/significanceThese 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

Gemma A Foulds

Brigitte T Doss

Alan G Pockley

Directory of Open Access Journals

Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B.

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

Gehrmann, M.

Stangl, S.

Kirschner, A.

Foulds, G. A.

Sievert, W.

Doss, B. T.

Walch, A.

Pockley, A. G.

Multhoff, G.

White Rose Research Online

Foulds, G.A.

Doß, B.T.

Walch, A.K.

Pockley, A.G.

PuSH

Crossref

Immunotherapeutic Targeting of Membrane Hsp70-Expressing Tumors Using Recombinant Human Granzyme B

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.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.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

Gehrmann Mathias

Stangl Stefan

Kirschner Andreas

Foulds Gemma A.

Sievert Wolfgang

Doß Brigitte T.

Walch Axel

Pockley Alan G.

Multhoff Gabriele

Public Library of Science (PLOS)

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Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B

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Nottingham Trent Institutional Repository (IRep)

Directory of Open Access Journals

White Rose Research Online

PuSH

Crossref

White Rose Research Online

Public Library of Science (PLOS)