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Intratumoral administration of the Toll-like receptor 7/8 agonist 3M-052 enhances interferon-driven tumor immunogenicity and suppresses metastatic spread in preclinical triple-negative breast cancer

journal contribution
posted on 12.11.2020, 00:01 by Damien J Zanker, Alex J Spurling, Natasha Brockwell, KL Owen, JM Zakhour, Tina RobinsonTina Robinson, HM Duivenvoorden, PJ Hertzog, SR Mullins, RW Wilkinson, Belinda Parker
© 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc. Objectives: Loss of tumor-inherent type I interferon (IFN) signalling has been closely linked to accelerated metastatic progression via decreased immunogenicity and antitumor immunity. Previous studies in murine models of triple-negative breast cancer (TNBC) demonstrate that systemic IFN inducers are effective antimetastatic agents, via sustained antitumor CD8+ T-cell responses. Repeated systemic dosing with recombinant IFNs or IFN inducers is associated with significant toxicities; hence, the use of alternate intratumoral agents is an active area of investigation. It is critical to investigate the impact of intratumoral agents on subsequent metastatic spread to predict clinical impact. Methods: In this study, the local and systemic impact of the intratumoral Toll-like receptor (TLR) 7/8 agonist 3M-052 alone or in combination with anti-PD1 was evaluated in metastatic TNBC models. The IFN-α receptor (IFNAR1) blocking antibody, MAR1-5A3, along with immune-deficient mice and ex vivo assays are utilised to examine the key targets of this agent that are critical for an antimetastatic response. Results: Single intratumoral administration of 3M-052 reduced mammary tumor growth, induced a T-cell-inflamed tumor microenvironment (TME) and reduced metastatic spread to lung. Metastasis suppression was reliant on IFN signalling and an antitumor immune response, in contrast to primary tumor growth inhibition, which was retained in NSG and CD8+ T-cell-depleted mice. 3M-052 action was demonstrated via dendritic cell activation and production of type I IFN and other pro-inflammatory cytokines to initiate a T-cell-inflamed TME and promote tumor cell antigen presentation. Conclusion: This work supports neoadjuvant TLR agonist-based immunotherapeutics as realistic options for immune activation in the TME and long-term metastatic protection in TNBC.

Funding

This work was supported by funding from Cancer Council Victoria (Grant-in-aid APP1127757; BS Parker), AstraZeneca and the Victorian Cancer Agency (Fellowship to BS Parker).

Cancer Council Victoria | APP1127757

AstraZeneca

Victorian Cancer Agency

History

Publication Date

28/09/2020

Journal

Clinical and Translational Immunology

Volume

9

Issue

9

Article Number

e1177

Pagination

20p.

Publisher

Wiley

ISSN

2050-0068

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.