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Research Article

Neoadjuvant Interferons: Critical for effective PD-1 based immunotherapy in TNBC

Natasha K. Brockwell, Katie L Owen, Damien Zanker, Alex Spurling, Jai Rautela, Hendrika M Duivenvoorden, Nikola Baschuk, Franco Caramia, Sherene Loi, Phillip K. Darcy, Elgene Lim and Belinda S. Parker
Natasha K. Brockwell
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University
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Katie L Owen
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University
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Damien Zanker
Department of Immunology, Monash University
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Alex Spurling
Garvan Institute of Medical Research
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Jai Rautela
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University
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Hendrika M Duivenvoorden
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University
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Nikola Baschuk
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University
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Franco Caramia
Cancer Immunology Program, Peter MacCallum Cancer Centre
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Sherene Loi
The University of Melbourne, Sir Peter MacCallum Department of Oncology
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Phillip K. Darcy
Department of Pathology, University of Melbourne
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Elgene Lim
St Vincent's Hospital, University of New South Wales
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Belinda S. Parker
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University
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  • For correspondence: Belinda.Parker@latrobe.edu.au
DOI: 10.1158/2326-6066.CIR-17-0150
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Abstract

The lack of targeted therapies available for triple-negative breast cancer (TNBC) patients who fail to respond to first-line chemotherapy has sparked interest in immunotherapeutic approaches. However, trials utilizing checkpoint inhibitors targeting the PD-1/PD-L1 axis in TNBC have had underwhelming responses. Here we investigated the interplay between type I IFN signaling and the PD-1/PD-L1 axis and tested the impact of combining IFN inducers, as immune activators, with anti-PD-1, to induce an antimetastatic immune response. Using models of TNBC, we demonstrated an interplay between type I IFN signaling and tumor cell PD-L1 expression that impacted therapeutic response. The data revealed that the type I IFN-inducer poly(I:C) was an effective immune activator and antimetastatic agent, functioning better than anti-PD-1, which was ineffective as a single agent. Poly(I:C) treatment induced PD-L1 expression on TNBC cells, and combined poly(I:C) and anti-PD-1 treatment prolonged metastasis-free survival in a neoadjuvant setting via the induction of a tumor-specific T-cell response. Use of this combination in a late treatment setting did not impact metastasis-free survival, indicating that timing was critical for immunotherapeutic benefit. Together, these data demonstrated anti-PD-1 as an ineffective single agent in preclinical models of TNBC. However, type I IFN inducers were effective immune activators and neoadjuvant trials combining them with anti-PD-1 to induce a sustained antitumor immune response are warranted.

  • Received March 27, 2017.
  • Revision received July 8, 2017.
  • Accepted August 21, 2017.
  • Copyright ©2017, American Association for Cancer Research.
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Published OnlineFirst August 28, 2017
doi: 10.1158/2326-6066.CIR-17-0150

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Neoadjuvant Interferons: Critical for effective PD-1 based immunotherapy in TNBC
Natasha K. Brockwell, Katie L Owen, Damien Zanker, Alex Spurling, Jai Rautela, Hendrika M Duivenvoorden, Nikola Baschuk, Franco Caramia, Sherene Loi, Phillip K. Darcy, Elgene Lim and Belinda S. Parker
Cancer Immunol Res August 28 2017 DOI: 10.1158/2326-6066.CIR-17-0150

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Neoadjuvant Interferons: Critical for effective PD-1 based immunotherapy in TNBC
Natasha K. Brockwell, Katie L Owen, Damien Zanker, Alex Spurling, Jai Rautela, Hendrika M Duivenvoorden, Nikola Baschuk, Franco Caramia, Sherene Loi, Phillip K. Darcy, Elgene Lim and Belinda S. Parker
Cancer Immunol Res August 28 2017 DOI: 10.1158/2326-6066.CIR-17-0150
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