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, Belinda S. Parker

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

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 affected therapeutic response. The data revealed that the type I IFN-inducer poly(I:C) was an effective immune activator and anti-metastatic 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.

Original languageEnglish
Pages (from-to)871-884
Number of pages14
JournalCancer Immunology Research
Volume5
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

Cite this

Brockwell, Natasha K. ; Owen, Katie L. ; Zanker, Damien ; Spurling, Alex ; Rautela, Jai ; Duivenvoorden, Hendrika M. ; Baschuk, Nikola ; Caramia, Franco ; Loi, Sherene ; Darcy, Phillip K. ; Lim, Elgene ; Parker, Belinda S. / Neoadjuvant interferons : Critical for effective PD-1–based immunotherapy in TNBC. In: Cancer Immunology Research. 2017 ; Vol. 5, No. 10. pp. 871-884.
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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 affected therapeutic response. The data revealed that the type I IFN-inducer poly(I:C) was an effective immune activator and anti-metastatic 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.",
author = "Brockwell, {Natasha K.} and Owen, {Katie L.} and Damien Zanker and Alex Spurling and Jai Rautela and Duivenvoorden, {Hendrika M.} and Nikola Baschuk and Franco Caramia and Sherene Loi and Darcy, {Phillip K.} and Elgene Lim and Parker, {Belinda S.}",
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Brockwell, NK, Owen, KL, Zanker, D, Spurling, A, Rautela, J, Duivenvoorden, HM, Baschuk, N, Caramia, F, Loi, S, Darcy, PK, Lim, E & Parker, BS 2017, 'Neoadjuvant interferons: Critical for effective PD-1–based immunotherapy in TNBC', Cancer Immunology Research, vol. 5, no. 10, pp. 871-884. https://doi.org/10.1158/2326-6066.CIR-17-0150

Neoadjuvant interferons : Critical for effective PD-1–based immunotherapy in TNBC. / Brockwell, Natasha K.; Owen, Katie L.; Zanker, Damien; Spurling, Alex; Rautela, Jai; Duivenvoorden, Hendrika M.; Baschuk, Nikola; Caramia, Franco; Loi, Sherene; Darcy, Phillip K.; Lim, Elgene; Parker, Belinda S.

In: Cancer Immunology Research, Vol. 5, No. 10, 01.10.2017, p. 871-884.

Research output: Contribution to journalArticleResearchpeer-review

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T2 - Critical for effective PD-1–based immunotherapy in TNBC

AU - Brockwell, Natasha K.

AU - Owen, Katie L.

AU - Zanker, Damien

AU - Spurling, Alex

AU - Rautela, Jai

AU - Duivenvoorden, Hendrika M.

AU - Baschuk, Nikola

AU - Caramia, Franco

AU - Loi, Sherene

AU - Darcy, Phillip K.

AU - Lim, Elgene

AU - Parker, Belinda S.

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