Abstract
Tumor-specific antibodies fused with IFN-β effectively treat antibody-resistant tumors.
Major finding: Tumor-specific antibodies fused with IFN-β effectively treat antibody-resistant tumors.
Mechanism: The anti-EGFR–IFN-β fusion antibody leads to dendritic cell–mediated CD8+ T-cell restimulation.
Impact: Tumor-targeted delivery of IFN-β may increase the efficacy of antibody-based cancer therapy.
Resistance often develops after extended tumor-specific antibody treatment. Yang and colleagues explored a strategy to treat antibody-resistant tumors based on reactivation of antitumor immune responses instead of tumor-intrinsic mechanisms. The authors established that type I IFNs mediate the antitumor responses of antibody treatment by showing that the efficacy of antibody treatment on antibody-sensitive tumors could be disrupted by blocking IFN receptor signaling. Additionally, local IFN-β expression sufficiently controlled tumor growth in antibody-resistant tumors. Based on these findings, a fusion protein of IFN-β and an EGF receptor (EGFR)–specific antibody was created to deliver IFN-β directly to tumors, as systemic administration of IFN-β has problematic side effects. Not only was the fusion antibody more effective than the first-generation anti-EGFR antibody cetuximab in several models of antibody-resistant tumors, including a KRAS-mutant model, it was also effective in breaking tolerance in EGFR-tolerized hosts. However, the fusion antibody was unable to control tumor growth in tumor-bearing mice lacking CD8+ T cells, suggesting that the effectiveness of anti-EGFR–IFN-β treatment depends on adaptive immunity and not induction of tumor cell apoptosis. Anti-EGFR–IFN-β–treated antigen presenting cells induced significantly more IFN-γ production by CD8+ T cells than anti-EGFR treated cells, indicating that IFN receptor–expressing dendritic cells are the primary target cells for anti-EGFR–IFN-β treatment, which stimulates them to reactivate antitumor responses by CD8+ T cells. Anti-EGFR–IFN-β treatment significantly increased expression of the T-cell inhibitory molecule programmed death-ligand 1 (PD-L1) in tumors, providing a potential explanation for why anti-EGFR–IFN-β–treated tumors eventually relapsed and raising the possibility that PD-L1 blockade could enhance the long-term efficacy of anti-EGFR–IFN-β. Indeed, the combination of anti-EGFR–IFN-β and anti-PD-L1 completely blocked tumor growth and enhanced the antitumor T-cell response. These findings provide a framework to increase tumor-specific antibody efficacy and circumvent antibody resistance by reactivating adaptive antitumor responses.
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