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Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity

Lookup NU author(s): Dr Rong Ou, Dr Caroline McCardle, Jack Minett, Dr Lei Huang, Emeritus Professor Andrew Mellor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Background: Activating the Stimulator of Interferon Genes (STING) adaptor incites anti-tumor immunity against immunogenic tumors in mice, prompting clinical trials to test STING activators. However, STING signalling in the tumor microenvironment (TME) during development of Lewis Lung Carcinoma (LLC) suppresses anti-tumor immunity to promote tumor growth. We hypothesized that local immune balance favoring suppression of anti-tumor immunity also attenuates anti-tumor responses following STING activation. The purpose of this study was to evaluate how STING activation impacts anti-tumor responses in mice bearing LLC tumors. Methods: Mice bearing established LLC tumors were treated with synthetic cyclic diadenyl monophosphate (CDA) to activate STING. Mice were monitored to assess LLC tumor growth, survival and protective anti-tumor immunity. Transcriptional and metabolic analyses were used to identify pathways responsive to CDA, and mice were co-treated with CDA and drugs that disrupt these pathways. Results: CDA slowed LLC tumor growth but most CDA-treated mice (77%) succumbed to tumor growth. No evidence of tumor relapse was found in surviving CDA-treated mice at experimental endpoints but mice were not immune to LLC challenge. CDA induced rapid increase in immune regulatory pathways involving Programmed Death-1 (PD-1), indoleamine 2,3 dioxygenase (IDO), and cyclo-oxygenase-2 (COX2) in the TME. PD-1 blockade enhanced anti-tumor responses to CDA and increased mouse survival but mice did not eliminate primary tumor burdens. Two IDO inhibitor drugs had little or no beneficial effects on anti-tumor responses to CDA. A third IDO inhibitor drug synergized with CDA to enhance tumor control and survival but mice did not eliminate primary tumor burdens. In contrast, co-treatments with CDA and the COX2-selective inhibitor Celecoxib controlled tumor growth, leading to uniform survival without relapse, and mice acquired resistance to LLC re-challenge and growth of distal tumors not exposed directly to CDA. Thus, mice co-treated with CDA and Celecoxib acquired stable and systemic anti-tumor immunity. Conclusions: STING activation incites potent anti-tumor responses and boosts local immune regulation to attenuate anti-tumor responses. Blocking STING-responsive regulatory pathways synergizes with CDA to enhance anti-tumor responses, particularly COX2 inhibition. Thus, therapy-induced resistance to STING may necessitate co-treatments to disrupt regulatory pathways responsive to STING in cancer patients.


Publication metadata

Author(s): Lemos H, Ou R, McCardle C, Lin Y, Calver J, Minett J, Chadli A, Huang L, Mellor AL

Publication type: Article

Publication status: Published

Journal: Journal for ImmunoTherapy of Cancer

Year: 2020

Volume: 8

Issue: 2

Online publication date: 26/08/2020

Acceptance date: 23/07/2020

Date deposited: 26/07/2020

ISSN (electronic): 2051-1426

Publisher: BMJ Group

URL: https://doi.org/10.1136/jitc-2020-001182

DOI: 10.1136/jitc-2020-001182


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