The University of Southampton
University of Southampton Institutional Repository

Antibodies to costimulatory receptor 4-1BB enhance anti-tumor immunity via T regulatory cell depletion and promotion of CD8 T cell effector function

Antibodies to costimulatory receptor 4-1BB enhance anti-tumor immunity via T regulatory cell depletion and promotion of CD8 T cell effector function
Antibodies to costimulatory receptor 4-1BB enhance anti-tumor immunity via T regulatory cell depletion and promotion of CD8 T cell effector function
The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic. Buchan et al. reveal dual anti-tumor activities for antibodies to the co-stimulatory receptor 4-1BB, which depend on antibody isotype and FcγR availability. Sequential scheduling of anti-4-1BB and checkpoint blockade mAbs, and antibodies engineered to harness both Treg cell depleting and effector cell agonism properties show potent anti-tumor activity in preclinical models, laying the groundwork for translation into the clinic.
1097-4180
958-970.e7
Buchan, Sarah
9ade187d-f127-45de-ad90-9d544d64718a
Dou, Lang
1e311f9c-adea-44be-a14a-9c8196eff7b8
Remer, Marcus
4ce5d442-0a24-4265-aaad-ad13c1936715
Booth, Steven
c2026d9d-ed93-4b1b-bce5-6b3efc8b8ca5
Dunn, Stuart N
b1dddfdc-8bcf-4bc5-8ff8-6a5b395ba45a
Lai, Chester
29ba48ea-2d38-497f-8cf9-400237f6a3a0
Semmrich, Monika
913807d9-6ff8-424e-b616-ede82babb94c
Teige, Ingrid
203d3295-4d50-4067-aea7-c7f4e0be8d1a
Martensson, Linda
b2bfc6e1-efa5-4f34-9d56-f78b90accd17
Penfold, Christine
400d743e-a639-45ea-a027-5b778800f6d3
Chan, H.T. Claude
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Willoughby, Jane
aa6969bd-3830-4e1b-83ac-6369b5711e1f
Mockridge, C. Ian
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Dahal, Lekh
1e993a7a-b007-4187-82ea-e28dd3920b66
Rogel, Anne
5a895ba8-c877-484f-a9c1-34a2b1af6414
Kannisto, Paivi
26e8f7e8-fd3b-4633-96f5-91aa5cd43b0c
Jernetz, Mats
b17d6e07-4e5d-44d3-9073-3cfab84c329d
Williams, Emily L
6e8d88b7-5d79-4625-b3aa-1de923aaaf37
Healy, Eugene
400fc04d-f81a-474a-ae25-7ff894be0ebd
Verbeek, J. Sjef
115ffb7c-4760-444f-888c-0798469e0b9c
Johnson, Peter
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Frendeus, Bjorn
3c6a6739-3319-4ae5-8019-d54470e2f444
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Gray, Juliet
12d5e17c-97bb-4d6d-8fc4-3914b730ed42
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Beers, Stephen
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Buchan, Sarah
9ade187d-f127-45de-ad90-9d544d64718a
Dou, Lang
1e311f9c-adea-44be-a14a-9c8196eff7b8
Remer, Marcus
4ce5d442-0a24-4265-aaad-ad13c1936715
Booth, Steven
c2026d9d-ed93-4b1b-bce5-6b3efc8b8ca5
Dunn, Stuart N
b1dddfdc-8bcf-4bc5-8ff8-6a5b395ba45a
Lai, Chester
29ba48ea-2d38-497f-8cf9-400237f6a3a0
Semmrich, Monika
913807d9-6ff8-424e-b616-ede82babb94c
Teige, Ingrid
203d3295-4d50-4067-aea7-c7f4e0be8d1a
Martensson, Linda
b2bfc6e1-efa5-4f34-9d56-f78b90accd17
Penfold, Christine
400d743e-a639-45ea-a027-5b778800f6d3
Chan, H.T. Claude
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Willoughby, Jane
aa6969bd-3830-4e1b-83ac-6369b5711e1f
Mockridge, C. Ian
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Dahal, Lekh
1e993a7a-b007-4187-82ea-e28dd3920b66
Rogel, Anne
5a895ba8-c877-484f-a9c1-34a2b1af6414
Kannisto, Paivi
26e8f7e8-fd3b-4633-96f5-91aa5cd43b0c
Jernetz, Mats
b17d6e07-4e5d-44d3-9073-3cfab84c329d
Williams, Emily L
6e8d88b7-5d79-4625-b3aa-1de923aaaf37
Healy, Eugene
400fc04d-f81a-474a-ae25-7ff894be0ebd
Verbeek, J. Sjef
115ffb7c-4760-444f-888c-0798469e0b9c
Johnson, Peter
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Frendeus, Bjorn
3c6a6739-3319-4ae5-8019-d54470e2f444
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
Gray, Juliet
12d5e17c-97bb-4d6d-8fc4-3914b730ed42
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Beers, Stephen
a02548be-3ffd-41ab-9db8-d6e8c3b499a2

Buchan, Sarah, Dou, Lang, Remer, Marcus, Booth, Steven, Dunn, Stuart N, Lai, Chester, Semmrich, Monika, Teige, Ingrid, Martensson, Linda, Penfold, Christine, Chan, H.T. Claude, Willoughby, Jane, Mockridge, C. Ian, Dahal, Lekh, Rogel, Anne, Kannisto, Paivi, Jernetz, Mats, Williams, Emily L, Healy, Eugene, Verbeek, J. Sjef, Johnson, Peter, Frendeus, Bjorn, Cragg, Mark, Glennie, Martin, Gray, Juliet, Al-Shamkhani, Aymen and Beers, Stephen (2018) Antibodies to costimulatory receptor 4-1BB enhance anti-tumor immunity via T regulatory cell depletion and promotion of CD8 T cell effector function. Immunity, 49 (5), 958-970.e7. (doi:10.1016/j.immuni.2018.09.014).

Record type: Article

Abstract

The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic. Buchan et al. reveal dual anti-tumor activities for antibodies to the co-stimulatory receptor 4-1BB, which depend on antibody isotype and FcγR availability. Sequential scheduling of anti-4-1BB and checkpoint blockade mAbs, and antibodies engineered to harness both Treg cell depleting and effector cell agonism properties show potent anti-tumor activity in preclinical models, laying the groundwork for translation into the clinic.

Text
Buchan et al Immunity Final Combined 210918 - Accepted Manuscript
Download (3MB)

More information

Accepted/In Press date: 20 September 2018
e-pub ahead of print date: 13 November 2018
Published date: 20 November 2018

Identifiers

Local EPrints ID: 425852
URI: http://eprints.soton.ac.uk/id/eprint/425852
ISSN: 1097-4180
PURE UUID: 090cd4c6-1e86-4ebc-986c-f54fba984e0d
ORCID for H.T. Claude Chan: ORCID iD orcid.org/0000-0003-0530-9480
ORCID for Jane Willoughby: ORCID iD orcid.org/0000-0002-6326-4519
ORCID for Peter Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Juliet Gray: ORCID iD orcid.org/0000-0002-5652-4722
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189
ORCID for Stephen Beers: ORCID iD orcid.org/0000-0002-3765-3342

Catalogue record

Date deposited: 05 Nov 2018 17:30
Last modified: 16 Mar 2024 07:13

Export record

Altmetrics

Contributors

Author: Sarah Buchan
Author: Lang Dou
Author: Marcus Remer
Author: Steven Booth
Author: Stuart N Dunn
Author: Chester Lai
Author: Monika Semmrich
Author: Ingrid Teige
Author: Linda Martensson
Author: Christine Penfold
Author: H.T. Claude Chan ORCID iD
Author: Jane Willoughby ORCID iD
Author: C. Ian Mockridge
Author: Lekh Dahal
Author: Anne Rogel
Author: Paivi Kannisto
Author: Mats Jernetz
Author: Emily L Williams
Author: Eugene Healy
Author: J. Sjef Verbeek
Author: Peter Johnson ORCID iD
Author: Bjorn Frendeus
Author: Mark Cragg ORCID iD
Author: Martin Glennie
Author: Juliet Gray ORCID iD
Author: Stephen Beers ORCID iD

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×