Brockwell et al. tested the Type I IFN-inducing TLR3 agonist poly(I:C) and anti-PD-1 against triple-negative breast cancer in preclinical models and found that while anti-PD-1 was ineffective as a single agent, it enhanced the antitumor effects of poly(I:C), activating NK cells, CD4+ T cells, and tumor-specific CD8+ T cells. Importantly, combination therapy prolonged survival only when administered as neoadjuvant therapy prior to primary tumor resection.
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.
Author Info: (1) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University. (2) Department of Biochemistry and Genetics, La Trobe Institute for Mole
Author Info: (1) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University. (2) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University. (3) Department of Immunology, Monash University. (4) Garvan Institute of Medical Research. (5) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University. (6) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University. (7) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre. (9) The University of Melbourne, Sir Peter MacCallum Department of Oncology. (10) Department of Pathology, University of Melbourne. (11) St Vincent's Hospital, University of New South Wales. (12) Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University Belinda.Parker@latrobe.edu.au.
