Augmenting interferon-β and anti-PD-L1 antibody bolsters non-ablative radiotherapy to leverage potent abscopal effect in metastatic cancers.

BACKGROUND: The abscopal effect is a systemic anti-tumor immune response induced by local radiotherapy (RT), resulting in regression of distant, non-irradiated tumors. Although ablative RT is more effective than conventionally fractionated RT in inducing this response, the underlying mechanisms remain incompletely understood, and strategies to enhance the abscopal effect following conventional RT are still needed. METHODS: We compared the immunological and therapeutic effects of ablative RT (15 Gy in a single fraction) and non-ablative RT (4 Gy in 10 fractions; biologically equivalent to 40 Gy) using murine breast cancer models. Tumor growth, immune cell infiltration, dendritic cell activation, cytokine expression and type I interferon signaling were analyzed. Functional studies were performed using CD8+ T cell depletion, IFNAR1 blockade, recombinant IFN-β administration and anti-PD-L1 treatment. RESULTS: Ablative radiation induced abscopal response characterized by significant suppression of distant tumor growth, whereas non-ablative RT failed to elicit this effect despite comparable local tumor control. The abscopal response depended on CD8+ T cells and was associated with increased infiltration of activated CD8+ T cells into distant tumors. Ablative RT promoted the recruitment and activation of CD11c+ dendritic cells, particularly CD103+ cells, in both tumors and draining lymph nodes. The cytokine qPCR array suggested that increased signaling of type I IFN and the mRNA and protein levels of type I IFN, specifically IFN-β significantly upregulated in tumor tissues irradiated with ablative radiation. Blocking IFNAR1 abolished the abscopal response, whereas administration of recombinant IFN-β restored the ability of sub-ablative RT to induce systemic anti-tumor immunity. Furthermore, combining recombinant IFN-β with anti-PD-L1 therapy significantly enhanced the therapeutic efficacy of sub-ablative RT in murine breast, colon, and lung cancer models. CONCLUSIONS: Our findings identify IFN-β as a critical mediator of RT-induced abscopal immunity and demonstrate that IFN-β supplementation can overcome the limited systemic efficacy of conventional fractionated RT. These results provide a rationale for combining IFN-β with radiotherapy and immune checkpoint blockade to enhance systemic anti-tumor immunity.