BAP1 as a predictive biomarker of therapeutic response to oncolytic vaccinia virus for metastatic renal cell carcinoma therapy

Abstract

BackgroundThe therapeutic efficacy of oncolytic vaccinia virus (JX-594) has been demonstrated in metastatic clear cell renal cell carcinoma (ccRCC); however, only selected patients respond, and there are no predictive biomarkers for therapeutic response. We aimed to identify predictive biomarkers for JX-594 treatment and elucidate the underlying mechanisms.MethodsFour cell line-derived xenograft (CDX) models were developed using representative ccRCC cell lines harboring common mutations. Tumors were subcutaneously implanted into the right flank of BALB/c nude mice. Mice were treated with vehicle or JX-594 via intratumoral injection on days 0, 3, and 6, and tumor growth was evaluated. Therapeutic efficacies of JX-594 and a STING agonist were compared in the BAP1-mutant (769-P) CDX model.ResultsAll four CDX models showed significant tumor shrinkage following JX-594 treatment versus control. JX-594 exhibited greater efficacy than the STING agonist in BAP1-deficient xenografts. The BAP1 mutation was associated with rapid tumor progression and a stronger response to JX-594. JX-594 induced IFN-beta expression through IRF7-dependent signaling in BAP1-deficient cells, bypassing impaired STING-IRF3 signaling.ConclusionsWe identified BAP1 as a potential predictive biomarker for JX-594 treatment and explored its underlying mechanisms. However, given that the study used immunodeficient models, the findings reflect tumor-intrinsic interferon responses and require further validation in immunocompetent models to assess immune microenvironment modulation and clinical relevance.