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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

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    Author
    Zanker, DJ; Spurling, AJ; Brockwell, NK; Owen, KL; Zakhour, JM; Robinson, T; Duivenvoorden, HM; Hertzog, PJ; Mullins, SR; Wilkinson, RW; ...
    Date
    2020-01-01
    Source Title
    Clinical and Translational Immunology
    Publisher
    WILEY
    University of Melbourne Author/s
    Owen, Katie; Parker, Belinda; Brockwell, Natasha; Zanker, Damien; Hertzog, Paul
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Microbiology and Immunology
    Metadata
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    Document Type
    Journal Article
    Citations
    Zanker, D. J., Spurling, A. J., Brockwell, N. K., Owen, K. L., Zakhour, J. M., Robinson, T., Duivenvoorden, H. M., Hertzog, P. J., Mullins, S. R., Wilkinson, R. W. & Parker, B. S. (2020). 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. CLINICAL & TRANSLATIONAL IMMUNOLOGY, 9 (9), https://doi.org/10.1002/cti2.1177.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/252594
    DOI
    10.1002/cti2.1177
    Abstract
    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.

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