Neoadjuvant interferons: Critical for effective PD-1–based Immunotherapy in TNBC

NK Brockwell, KL Owen, D Zanker, A Spurling… - Cancer immunology …, 2017 - AACR
NK Brockwell, KL Owen, D Zanker, A Spurling, J Rautela, HM Duivenvoorden, N Baschuk…
Cancer immunology research, 2017AACR
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 …
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 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. Cancer Immunol Res; 5(10); 871–84. ©2017 AACR.
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