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STING activation reverses lymphoma-mediated resistance to antibody immunotherapy

STING activation reverses lymphoma-mediated resistance to antibody immunotherapy
STING activation reverses lymphoma-mediated resistance to antibody immunotherapy

Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis and metastasis. Macrophages are also the key effector cell for monoclonal antibody (mAb) therapies. Here we report that the tumor microenvironment creates an immunosuppressive signature on tumor-associated macrophages (TAM) which favors expression of inhibitory rather than activating Fcγ receptors (FcγR), thereby limiting the efficacy of mAb immunotherapy. We assessed a panel of TLR and STING agonists (a) for their ability to reprogram macrophages to a state optimal for mAb immunotherapy. Both STINGa and TLRa induced cytokine release, modulated FcγR expression and augmented mAb-mediated tumor cell phagocytosis in vitro. However, only STINGa reversed the suppressive FcγR profile in vivo, providing strong adjuvant effects to anti-CD20 mAb in murine models of lymphoma. Potent adjuvants like STINGa which can improve FcγR activatory:inhibitory (A:I) ratios on TAM are appealing candidates to reprogram TAM and curb tumor-mediated immunosuppression, thereby empowering mAb efficacy.

Journal Article
0008-5472
3619-3631
Dahal, Lekh N
1e993a7a-b007-4187-82ea-e28dd3920b66
Dou, Lang
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Hussain, Khiyam
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Liu, Rena
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Earley, Alexander
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Cox, Kerry L
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Murinello, Salome
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Tracy, Ian
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Forconi, Francesco
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Steele, Andrew J
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Duriez, Patrick
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Gomez-Nicola, Diego
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Teeling, Jessica L
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Glennie, Martin J
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Cragg, Mark S
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Beers, Stephen A
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Dahal, Lekh N
1e993a7a-b007-4187-82ea-e28dd3920b66
Dou, Lang
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Hussain, Khiyam
9468f252-81d0-4251-b800-702433b610f8
Liu, Rena
5df6e854-e60f-4bee-96ed-72906879fc10
Earley, Alexander
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Cox, Kerry L
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Murinello, Salome
3888deb4-db98-40c9-a04c-e4e72da3aebd
Tracy, Ian
38b326f8-e8c6-4a86-8e6c-35bebe110f9f
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Steele, Andrew J
4349f6aa-2e3a-49a8-be73-7716056ae089
Duriez, Patrick
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Gomez-Nicola, Diego
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Teeling, Jessica L
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Glennie, Martin J
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cragg, Mark S
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Beers, Stephen A
a02548be-3ffd-41ab-9db8-d6e8c3b499a2

Dahal, Lekh N, Dou, Lang, Hussain, Khiyam, Liu, Rena, Earley, Alexander, Cox, Kerry L, Murinello, Salome, Tracy, Ian, Forconi, Francesco, Steele, Andrew J, Duriez, Patrick, Gomez-Nicola, Diego, Teeling, Jessica L, Glennie, Martin J, Cragg, Mark S and Beers, Stephen A (2017) STING activation reverses lymphoma-mediated resistance to antibody immunotherapy. Cancer Research, 77 (13), 3619-3631. (doi:10.1158/0008-5472.CAN-16-2784).

Record type: Article

Abstract

Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis and metastasis. Macrophages are also the key effector cell for monoclonal antibody (mAb) therapies. Here we report that the tumor microenvironment creates an immunosuppressive signature on tumor-associated macrophages (TAM) which favors expression of inhibitory rather than activating Fcγ receptors (FcγR), thereby limiting the efficacy of mAb immunotherapy. We assessed a panel of TLR and STING agonists (a) for their ability to reprogram macrophages to a state optimal for mAb immunotherapy. Both STINGa and TLRa induced cytokine release, modulated FcγR expression and augmented mAb-mediated tumor cell phagocytosis in vitro. However, only STINGa reversed the suppressive FcγR profile in vivo, providing strong adjuvant effects to anti-CD20 mAb in murine models of lymphoma. Potent adjuvants like STINGa which can improve FcγR activatory:inhibitory (A:I) ratios on TAM are appealing candidates to reprogram TAM and curb tumor-mediated immunosuppression, thereby empowering mAb efficacy.

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More information

Accepted/In Press date: 19 April 2017
e-pub ahead of print date: 16 May 2017
Published date: July 2017
Keywords: Journal Article

Identifiers

Local EPrints ID: 412212
URI: http://eprints.soton.ac.uk/id/eprint/412212
ISSN: 0008-5472
PURE UUID: f2fbdde6-2f07-401f-b502-fc7095becda9
ORCID for Ian Tracy: ORCID iD orcid.org/0000-0003-4624-672X
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831
ORCID for Andrew J Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Patrick Duriez: ORCID iD orcid.org/0000-0003-1814-2552
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682
ORCID for Jessica L Teeling: ORCID iD orcid.org/0000-0003-4004-7391
ORCID for Mark S Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Stephen A Beers: ORCID iD orcid.org/0000-0002-3765-3342

Catalogue record

Date deposited: 13 Jul 2017 16:31
Last modified: 16 Mar 2024 04:14

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Contributors

Author: Lekh N Dahal
Author: Lang Dou
Author: Khiyam Hussain
Author: Rena Liu
Author: Alexander Earley
Author: Kerry L Cox
Author: Salome Murinello
Author: Ian Tracy ORCID iD
Author: Andrew J Steele ORCID iD
Author: Patrick Duriez ORCID iD
Author: Mark S Cragg ORCID iD
Author: Stephen A Beers ORCID iD

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