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 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. .

Intratumoral administration of the Toll‐like receptor 7/8 agonist 3M‐052 enhances interferon‐driven tumor immunogenicity and suppresses metastatic spread in preclinical triple‐negative breast cancer

“…Treatment with 3M-052 alone and in combination with anti-PD1 reduced primary tumor size at the time of resection (Figure 2b), and this was supported by reduced expression of the proliferative marker Ki67 and elevated c-caspase-3 expression ( Figure 2c). As previously reported in this model, 26 single-agent anti-PD1 did not alter primary tumor growth or proliferation (Figure 2b and c). We next evaluated the impact of combination versus single-agent therapy on metastatic spread post-primary tumor resection.…”

“…3M-052 treatment enhanced the infiltration of NK, B and T cellsincluding CD8 + T cellswhilst changes in Ly6G + myeloid cell infiltrates were not observed ( Figure 1d). As expected from enhanced IFN signalling [given PD-L1 and PD1 are documented IFN-stimulated genes (ISGs) 26,34,35 ], elevated PD1 was observed in the treatment group ( Figure 1c, Supplementary figure 2i and j). Importantly, the impact of 3M-052 intratumoral administration was not limited to the primary tumor.…”

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

“…The jury is still out on the cellular impact and long-term clinical benefits of such compounds, particularly in regards to their use in combinatorial strategies and the promotion of autoimmunity, inflammation, and malignant cell survival in the TME [189]. Nevertheless, positive preclinical data [179,180,[189][190][191] support the use of TLR-induction of JAK-STAT pathways to boost antitumor immunity, especially in metastatic settings, in which tumors are largely unreactive or immune-poor.…”

“…In fact, many JAKinibs that have shown promise in preclinical and early patient trials have failed to progress due to high toxicity and off-target immune-suppression, such as the JAK2 inhibitor, AZD1480 [152,208], which was shown to potently suppress both STAT1 and STAT3 signaling [209]. Such reports are increasingly salient, given the importance of retained type I IFN signaling in the TME to the efficacy of checkpoint inhibitors [190,210] that are often utilized in conjunction with JAKinibs, which JAK inhibition is likely to impede. As such, it might be unsurprising that no JAKinibs are currently FDA approved for cancer, despite their widespread usage in myelofibrosis.…”

Chemotherapy-induced immunological breast cancer dormancy: a new function for old drugs?

“…However, because the number of potential neoantigens available for immune response in most breast cancers, responses are modest compared with other cancers such as lung and melanoma, the use of check-point inhibitors may require combination with other therapies [269] . Therefore, combination with neo-adjuvant chemotherapy (causing the release of tumor antigens), antiangiogenesis therapies (suppressing inhibitory cues) [182] or Type I IFN (acting immunostimulating) [270] may be more effective and should be explored.…”