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Neoadjuvant interferons: critical for effective PD-1 based immunotherapy in TNBC

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.

Type Journal
ISBN 2326-6074 (Electronic) 2326-6066 (Linking)
Authors Brockwell, N. K.; Owen, K. L.; Zanker, D.; Spurling, A.; Rautela, J.; Duivenvoorden, H. M.; Baschuk, N.; Caramia, F.; Loi, S.; Darcy, P. K.; Lim, E.; Parker, B. S.
Responsible Garvan Author A/Prof Elgene Lim
Publisher Name Cancer Immunology Research
Published Date 2017-10-31
Published Volume 5
Published Issue 10
Published Pages 871-884
Status Published in-print
DOI 10.1158/2326-6066.CIR-17-0150
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/28848054