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.

Autor: Zanker DJ; Sir Peter MacCallum Department of Oncology University of Melbourne Parkville VIC Australia.; Cancer Immunology and Therapeutics Programs Peter MacCallum Cancer Centre Melbourne VIC Australia., Spurling AJ; Cancer Immunology and Therapeutics Programs Peter MacCallum Cancer Centre Melbourne VIC Australia., Brockwell NK; Sir Peter MacCallum Department of Oncology University of Melbourne Parkville VIC Australia.; Cancer Immunology and Therapeutics Programs Peter MacCallum Cancer Centre Melbourne VIC Australia., Owen KL; Sir Peter MacCallum Department of Oncology University of Melbourne Parkville VIC Australia.; Cancer Immunology and Therapeutics Programs Peter MacCallum Cancer Centre Melbourne VIC Australia., Zakhour JM; Department of Biochemistry and Genetics La Trobe Institute for Molecular Science La Trobe University Melbourne VIC Australia., Robinson T; Department of Biochemistry and Genetics La Trobe Institute for Molecular Science La Trobe University Melbourne VIC Australia., Duivenvoorden HM; Department of Biochemistry and Genetics La Trobe Institute for Molecular Science La Trobe University Melbourne VIC Australia.; School of Biological Sciences Monash University Clayton VIC Australia., Hertzog PJ; Centre for Innate Immunity and Infectious Diseases Hudson Institute of Medical Research Clayton VIC Australia., Mullins SR; R&D Oncology AstraZeneca Ltd Cambridge UK., Wilkinson RW; R&D Oncology AstraZeneca Ltd Cambridge UK., Parker BS; Sir Peter MacCallum Department of Oncology University of Melbourne Parkville VIC Australia.; Cancer Immunology and Therapeutics Programs Peter MacCallum Cancer Centre Melbourne VIC Australia.; Department of Biochemistry and Genetics La Trobe Institute for Molecular Science La Trobe University Melbourne VIC Australia.
Jazyk: angličtina
Zdroj: Clinical & translational immunology [Clin Transl Immunology] 2020 Sep 28; Vol. 9 (9), pp. e1177. Date of Electronic Publication: 2020 Sep 28 (Print Publication: 2020).
DOI: 10.1002/cti2.1177
Abstrakt: 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.
Competing Interests: Financial support and reagents were provided by AstraZeneca. SRM and RWW are employed by AstraZeneca Ltd.
(© 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)
Databáze: MEDLINE
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